diff --git a/2016-09-24-lecture02.md b/2016-09-24-lecture02.md index 72053ef..89d385f 100644 --- a/2016-09-24-lecture02.md +++ b/2016-09-24-lecture02.md @@ -9,6 +9,8 @@ Last time we learned some of the basic cellular anatomy of the nervous system. T First of all it is a system of systems. In other words… +TODO: exchange pngs for jpgs in this document + --- ## Major components of the nervous system and their functional relationships @@ -416,11 +418,11 @@ Note: substantia nigra pars compacta, a nucleus containing neurons making the neurotransmitter dopamine that are important for regulating motor movements via their connections with the basal ganglia and which are devastated in parkinson’s disease. -Now you’ve all heard the phrase ‘running around like a chicken with its head cut off’ —> - *dark appearance due to high levels of dark pigment neuromelanin in dopaminergic neurons* *Neuromelanin is directly biosynthesized from L-DOPA, precursor to dopamine, by tyrosine hydroxylase (TH)* +Now you’ve all heard the phrase ‘running around like a chicken with its head cut off’ —> + --- ## The brainstem is all you need to live @@ -635,12 +637,11 @@ Note:
Fiber stain
[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)
-
Dorsal view
Neuroscience 5e Fig. A11
+
Dorsal view
Neuroscience 5e Fig. A11
-
Dorsal view cut away
Neuroscience 5e Fig. A11
- -
MRI-DTI dorsal projection
Neuroscience 5e
+
Dorsal view cut away
Neuroscience 5e Fig. A11
+
MRI-DTI dorsal projection
Neuroscience 5e
Note: @@ -681,7 +682,7 @@ anterior commisure -
Neuroscience 5e Fig. 26.1
+
Neuroscience 5e Fig. 26.1
Note: @@ -689,7 +690,7 @@ Note: ## Brain organization summary -
Neuroscience 5e Fig. A12
+
Neuroscience 5e Fig. A12
Pinky and the Brain
@@ -720,7 +721,7 @@ Note:
Cells
-
Cells & fibers
Meynert 1884
+
Cells & fibers
Meynert 1884
Golgi stain
Jones 1981
@@ -746,7 +747,7 @@ Note: -
Olson and Walsh, 2002 Fig. 2
+
Olson and Walsh, 2002 Fig. 2
Note: @@ -825,7 +826,7 @@ He used cell body staining like the Nissl stain to examine differences in genera ## Brodmann areas -
Brodmann 1909
+
Brodmann 1909
Brodmann 1909 color
@@ -880,7 +881,9 @@ Note: ## Major brain areas involved in the comprehension and production of language -
Neuroscience 5e Fig. 27.1
+
Neuroscience 5e Fig. 27.1
+ + Note: @@ -891,7 +894,7 @@ Note: ## Characteristics of Broca's and Wernicke's aphasias -
Neuroscience 5e Table 27.1
+
Neuroscience 5e Table 27.1
Note: @@ -1006,8 +1009,7 @@ And since each side of the brain to some degree can work independently of the ot ## Confirmation of hemispheric specialization for language -
Neuroscience 5e Fig. 27.3
- +
Neuroscience 5e Fig. 27.3
Note: @@ -1047,7 +1049,8 @@ Babbling sounds from a baby shows that there is a pattern of sounds produced seq ## Mapping brain activity with fMRI -
Neuroscience 5e Fig. 27.6
+
Neuroscience 5e Fig. 27.6
+ Note: diff --git a/2016-11-03-extra.md b/2016-11-03-extra.md index ae81ed2..8c81371 100644 --- a/2016-11-03-extra.md +++ b/2016-11-03-extra.md @@ -1,3 +1,11 @@ +## Cerebral circulation +
Neuroscience 5e Fig. A17
+
Neuroscience 5e Fig. A17
+
Neuroscience 5e Fig. A17
+
Neuroscience 5e Fig. A17
+
Neuroscience 5e Fig. A18
+ + ## Brain damage and visual perception diff --git a/2016-11-18-lecture16.md b/2016-11-18-lecture16.md index 80daeec..27fc029 100644 --- a/2016-11-18-lecture16.md +++ b/2016-11-18-lecture16.md @@ -1,93 +1,78 @@ -## What does the basal ganglia do? +## Modulation of movement by the basal ganglia -* Modulate the initiation, termination, amplitude, and selection of movement -* Initiation and selection -* Learning -* Response-outcome associations -* Stimulus-response associations -* Used in dopamine circuits +
+
+ +* Basal ganglia are a large set of nuclei that lie deep within the cerebral hemispheres + * Consists of striatum (**caudate**, **putamen**) and the **globus pallidus** +* Together with the **substantia nigra** and the **subthalamic nucleus** comprises the **basal ganglia system** which links most areas of the cortex with upper motor neurons of the frontal cortex +* Basal ganglia influence movements by regulating the activity of upper motor neurons + * Modulate the **initiation** and **termination** of movement +* Proper basal ganglia function required for normal voluntary movements +* Disorders of basal ganglia or associated structures result in upper motor neurons not switching smoothly between movement initation and termination commands + +
Note: +- also with the non-motor loops (limbic system class): +* Learning, reward mechanisms + * Response-outcome associations + * Stimulus-response associations + [http://www.youtube.com/watch?v=Td4QGHNJ8Q0](http://www.youtube.com/watch?v=Td4QGHNJ8Q0) +* Modulate the initiation, termination, amplitude, and selection of movement + +*and selection of movement* +*Used in dopamine circuits* + -- ## Overall organization of neural structures that control movement
Neuroscience 5e Fig. 16.1
- Note: Today we will begin our examination of the pathways in the nervous system that modulate and give rise to volitional control of our skeletal muscles. --- -## Basal ganglia and the control of movement +## Basal ganglia and the control of movement– objectives -* Anatomy -* Basal Ganglia components * Anatomical connectivity * Function– modulation through disinhibition * Neuromodulators– dopamine * Diseases of the basal ganglia -* Other disinhibition loops + Note: We will discuss… ---- - -## Modulation of movement by the basal ganglia - -* Basal ganglia do not project directly to the spinal cord, instead they influence movements by regulating the activity of upper motor neurons -* The basal ganglia are a large set of nuclei that lie deep within the cerebral hemispheres -* Three main nuclei– caudate, putamen, and the globus pallidus -* Together with the substantia nigra and the subthalamic nucleus make a loop that links most areas of the cortex with upper motor neurons -* These neurons are required for the normal course of voluntary movements. Supervise motor movements - -Note: - - +* Basal Ganglia components +* Other disinhibition loops --- ## Corpus striatum -* Corpus striatum (striped body)– contains two main nuclei, the caudate and putamen. These two areas are the input zone of the basal ganglia -* Most all areas of the cortex project here. Prominent innervation from the associational cortical areas of the frontal and parietal lobes. Collectively called the corticostriatal pathway. The receiving neurons are called medium spiny neurons. Large dendritic trees, integrate information form a variety of structures +* Corpus striatum ('striped body') contains two nuclei– the caudate and putamen +* Function as the input zones for the basal ganglia +* Most regions of the cortex project to the striatum. Prominent innervation from the associational cortical areas of the frontal and parietal lobes. Collectively called the corticostriatal pathway +* Neurons in striatum that receive corticostriatal input are called medium spiny neurons. Large dendritic trees, integrate information form a variety of structures Note: - ---- +-- ## Most cortical areas project to striatum -* Most cortical areas (except A1 and V1) project to the corpus striatum +Most cortical areas project to the striatum, except for primary auditory cortex (A1) and primary visual cortex (V1). -Neuroscience 2001e - -
- -Note: - - - ---- - -## Anatomical location of the basal ganglia - -Neuroscience 2001e - -
- -
- -
+
Neuroscience 2e 2001
Note: @@ -96,70 +81,53 @@ Note: ## Anatomical location of the basal ganglia -Neuroscience 5e Fig. 18.1 +
Neuroscience 5e Fig. A14
Note: - --- -## Anatomy of the basal ganglia:caudate and putamen +## Anatomy of the basal ganglia: caudate and putamen -Neuroscience 5e Fig. 18.1 +
Neuroscience 5e Fig. 18.1
-
- -
Note: -Striatum: caudate and putamen +TODO: human brain section from MSU? -Make up what type of nuclei? (input) +Main inputs: Striatum– caudate and putamen -Globus Pallidus interna and substantia nigra pars reticulata +Main outputs of basal ganglia system include: Globus pallidus interna (thalamus) and substantia nigra pars reticulata (superior colliculus, eye movements) -Make up what type of nuclei? (output) - -Globus pallidus externa, STN, and substantia nigra pars compacta - -make up what nuclei? (intermediate) +Intermediate nuclei in the basal ganglia system: Globus pallidus externa, STN, and substantia nigra pars compacta --- ## Striatum: medium spiny neurons * Medium spiny neurons (MSNs) located in caudate and putamen -* ~90% of neurons in striatum; primary projection neurons -* GABAergic; inhibitory -* Very little spontaneous activity; dependent on excitatory input for discharge +* ~90% of neurons in striatum. Project to globus pallidus +* GABAergic, inhibitory +* Very little spontaneous activity. Dependent on excitatory input for discharge * Large dendritic trees -* Inputs from cortical, thalamic, and brainstem structures -
- -
- -
+
Note: +TODO: + +Kreitzer Ann Rev Neurosci 2009 + [lower spine image: http://en.wikipedia.org/wiki/Image:Spines.jpg](http://en.wikipedia.org/wiki/Image:Spines.jpg) ---- - -## Medium spiny neuron in the corpus striatum - -
- -
- -
- -Note: +*Inputs from cortical, thalamic, and brainstem structures?* +Medium spiny neuron in the corpus striatum +TODO: mine or other image --- @@ -177,18 +145,11 @@ Note: ## Organization of inputs to basal ganglia -Neuroscience 5e Fig. 18.2 - - - -
+
Neuroscience 5e Fig. 18.2
Note: - - ---- - + --- ## Projections from MSNs -* MSNs of caudate and putamen give rise to inhibitory GABAergic projections that terminate in a pair of nuclei within the basal ganglia called the globus pallidus (external and internal segments) and a region of the substantia nigra called the pars reticulata which in turn contain the major output neurons of the basal ganglia -* On average more than 100 MSNs converge onto each neuron in the globus pallidus -* Globus pallidus (GP) internal neurons then convey information back to the cortex via the thalamus (ventral lateral and ventral anterior nuclei) to make a loop +* MSNs of caudate and putamen give rise to inhibitory GABAergic projections that terminate in a pair of nuclei within the basal ganglia called the globus pallidus (GP) and a region of the substantia nigra called the pars reticulata (SNr) +* Approximately 100 MSNs converge onto each neuron in the globus pallidus +* Globus pallidus contains two nuclei– GP externa (GPe) and GP interna (GPi) +* The GPi and the SNr contain the main output neurons of the basal ganglia +* Globus pallidus interna (GPi) neurons then convey information back to the cortex via the thalamus (ventral lateral and ventral anterior nuclei, VA/VL) to make a loop Note: - --- ## MSNs send projections to the globus pallidus and pars reticulata -Neuroscience 5e Fig. 18.3 +
Neuroscience 5e Fig. 18.3
- -
- Note: @@ -231,9 +188,10 @@ Note: ## The direct pathway -* Substantia nigra (SN) pars reticulata neurons project to upper motor neurons in the Superior colliculus that command eye movements without going to the thalamus -* Globus pallidus (GP) and pars reticulata neurons are GABAergic. Unlike MSNs they have high levels of spontaneous activity that normally are used to prevent unwanted movementsThus the output from the basal ganglia is normally inhibitory -* When MSNs fire (in anticipation of movement) this inhibits the inhibition (disinhibition) and allows upper motor neurons to send commands to local circuit and lower motor neurons that initiate movement +* Substantia nigra pars reticulata (SNr) neurons project to upper motor neurons in the superior colliculus that command eye movements without going to the thalamus +* **Globus pallidus and pars reticulata neurons are GABAergic**. Unlike MSNs they have high levels of spontaneous activity– they are tonically active +* Thus the output from the basal ganglia is normally inhibitory-- tonic inhibition +* When MSNs fire (in anticipation of movement) this inhibits the inhibition (**disinhibition**) and allows upper motor neurons to send commands to local circuit and lower motor neurons that initiate movement * Called the direct pathway Note: @@ -244,116 +202,69 @@ Note: ## Direct pathway of outputs from the basal ganglia -Neuroscience 5e Fig. 18.4 +
Neuroscience 5e Fig. 18.4
- -
- Note: --- -## Example of a disinhibitory circuit… +## Example of a disinhibitory circuit -Neuroscience 5e Fig. 18.5 +
Neuroscience 5e Fig. 18.5
- -
- Note: --- -## Disinhibitory interaction in basal ganglia regulates downstream activity in downstream motor centers +## Basal ganglia disinhibition and the initiation of movement commands in upper motor neurons + +
Histograms of spike frequency in +caudate, SNr, SC during eye movements +
Neuroscience 5e Fig. 18.6
+ + +Note: [http://www.youtube.com/watch?v=P6uTlnyNaTs](http://www.youtube.com/watch?v=P6uTlnyNaTs) -Neuroscience 5e Fig. 18.6 - - - -
- -Note: - - --- -## Direct excitatory pathway via disinhibition +## Disinhibition through the direct pathway increases activity in upper motor neurons -* Turns up motor activity +
Direct pathway: ctx --> putamen --> GPi --> VA/VL --> ctx
J. Ackman [CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)
- - - - - - - -
- Note: -Overall excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement) - ---- - -## Direct and indirect pathways through the basal ganglia - -Dopamine excites the direct and inhibits the indirect pathway - - - -Neuroscience 5e Fig. 18.7 - - - -
- -Note: - - +Overall excitatory by disinhibiting the upper motor neurons in the cortex (promotes movement, initiation of motor commands) --- ## Indirect pathway circuits -* Provides a second route of influence via a loop back to the direct pathway. -* MSN project also to the globus pallidus external nuclei which then project to the subthalamic nucleus of the ventral thalamus. -* Subthalamic nucleus projects to globus pallidus internal which then projects out of basal ganglia to the VA/VL complex of the thalamus. -* Subthalamic projections are excitatory which increases the inhibition of Globus pallidus. Opposite of the direct pathway. Acts as a brake to prevent too much disinhibition of upper motor neurons. -* Turns down motor activity. +* Provides a second route of influence via a loop back to the direct pathway +* MSN neurons also project to the globus pallidus external (GPe) nuclei which then project to the subthalamic nucleus (STN) of the ventral thalamus +* STN neurons project back to GPi which then projects out of basal ganglia to the VA/VL complex of the thalamus +* **Subthalamic projections are excitatory which increases the inhibition of GPi**. Opposite/antagonistic of the direct pathway. Acts as a brake to prevent too much disinhibition of upper motor neurons +* Decreases upper motor neuron activity Note: - --- ## Indirect pathway +
Indirect pathway: ctx --> putamen --> GPe --> STN --> GPi --> VA/VL --> ctx
J. Ackman [CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)
- - - - - - - - - - -
- Note: Overall inhibitory. Serves to modulate the disinihibitory actions of the direct pathway @@ -362,22 +273,13 @@ Overall inhibitory. Serves to modulate the disinihibitory actions of the direct ## Center–surround functional organization of the direct and indirect pathways -Neuroscience 5e Fig. 18.\8 +
Neuroscience 5e Fig. 18.8
- -
- Note: think center-surround receptive fields for luminance contrast in retinal ganglion cells mediated by synaptic interactions between photoreceptors, bipolar cells, and horizontal cells in the outer plexiform layer. - - - - - - -difference of Gaussians is a feature enhancement algorithm -mexican hat distribution (shaped like a sombrero) @@ -388,307 +290,181 @@ think center-surround receptive fields for luminance contrast in retinal ganglio [-automatic scale selection in computer vision applications; see Laplacian of Gaussian https://en.wikipedia.org/wiki/Mexican_hat_wavelet](https://en.wikipedia.org/wiki/Mexican_hat_wavelet) - - Attentional field has a Mexican hat distribution http://www.sciencedirect.com/science/article/pii/S0042698904005735 - - ---- - -## Hemiballismus: violent involuntary movements of the limbs - -* Defects in the subthalamic nucleus of the contralateral side of the movements - - - - - - - - - - - - - - - - - -Note: - - - --- ## Dopaminergic neurons modulate direct and indirect pathways -* Medium spiny neurons in striatum project to the substantia nigra pars compacta, which in turn projects back to sets of medium spiny neurons. -* Both spiny neurons that project to internal and external globus pallidus receive these inputs. -* Those that project to internal globus pallidus have type D1 receptors (coupled to a Gαs, excitatory) and those that project to external globus pallidus use type D2 receptors (Gαi, inhibitory). +* Medium spiny neurons (MSNs) in striatum project to the substantia nigra pars compacta (SNc), which in turn projects back to MSNs +* Both MSNs that project to GPe and GPi receive these inputs +* Those that project to GPi have type D1 receptors (coupled to a Gαs, excitatory) and those that project to GPe use type D2 receptors (Gαi, inhibitory) * Dopamine excites the direct and inhibits the indirect pathway Note: - - ---- +-- ## Effector pathways associated with G-protein-coupled receptors -specificity at the level of the α subunit +
Specificity at the level of the G protein α subunit. +D1 uses Gs, D2 uses Gi G-proteins
+
Neuroscience 5e Fig. 7.6
-Like D1 receptors - -Neuroscience 2001 - - - -D2 receptors - -
Note: - --- -## Dopamine used by the direct pathway to excite medium spiny neurons +## Direct and indirect pathways through the basal ganglia +Dopamine excites the direct and inhibits the indirect pathway. + +
Neuroscience 5e Fig. 18.7
- - - - -SN - -pars - -compacta - -dopamine (+) - -
- -
- Note: + --- -## Disinhibition in direct and indirect pathways through the basal ganglia +## Synaptic input to striatal medium spiny neurons -Neuroscience 5e Fig. 18.7 - - - -
+
Smith and Bolam, 1990
Note: - ---- - -## Disinhibition in direct and indirect pathway through the basal ganglia - -Dopamine excites the direct and inhibits the indirect pathway - - - -Neuroscience 5e Fig. 18.7 - - - -Note: - - - --- ## Motor behavior is determined by the balance between direct/indirect striatal outputs * Hypokinetic disorders (decreased movement) -* insufficient direct pathway output -* excess indirect pathway output -* Hyperkinetic disorders (excess movement) -* excess direct pathway output -* insufficient indirect pathway output + * Insufficient direct pathway output + * Excess indirect pathway output +* Hyperkinetic disorders (excess movement) + * Excess direct pathway output + * Insufficient indirect pathway output Note: +--- + +## Hemiballismus: violent involuntary movements of the limbs + +Defects in the subthalamic nucleus contralateral to the involuntary movements. Reduced indirect pathway function. + +
J. Ackman [CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)
+ +Note: + +damage to STN results in violent involuntary movements of the limbs. --- ## Parkinson’s disease -* Pathophysiology is the loss of nigrostriatal dopaminergic projections +* Due to the degeneration of dopaminergic neurons of the substantia nigra pars compacta +* Leads to tremors, slowness of movements, rigidity of extremities and neck, minimal facial expressions +* Slowly progressing disease +* Some success in slowing the progression comes from the use of Levadopa (L-DOPA)– gets converted to dopamine and gets to dopamine receptors in basal ganglia -SNc +
Neuroscience 5e Fig. 18.9
- -Striatum - -Michael J. Fox - -Muhammad Ali - -Pope John Paul II - -Janet Reno - -Katherine Hepburn - -
- -
- -
- -
- -
- -
- -Note: - - - ---- - -## Parkinson’s disease - -* Due to the degeneration of dopaminergic neurons of the substantia nigra pars compacta. -* Leads to tremors, slowness of movements, rigidity of extremities and neck, minimal facial expressions. -* Slowly progressing disease. -* Some success in slowing the progression comes from the use of Levadopa (L-DOPA)– gets converted to dopamine and gets to dopamine receptors in basal ganglia. - -
- Note: [from https://en.wikipedia.org/wiki/Substantia_nigra](https://en.wikipedia.org/wiki/Substantia_nigra) >Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. ---- +-- -## Summary explanation of hypokinetic and hyperkinetic disorders +## Parkinson’s disease -
+Pathophysiology is the loss of nigrostriatal dopaminergic projections from SNc + +
Michael J. Fox
+ +
Muhammad Ali
+ +
Katherine Hepburn
Note: - +hypokinetic, failure of disinhibition. dimin facial expressions, slow shuffling movements, no arm swinging during walking --- +## Parkinson’s- loss of dopamine making neurons in the midbrain's substantia nigra + + + +
B. Crawford and K. McBurney, Univ. of Victoria
+ +Note: + +substantia nigra pars compacta, a nucleus containing neurons making the neurotransmitter dopamine that are important for regulating motor movements via their connections with the basal ganglia and which are devastated in parkinson’s disease. + +*dark appearance due to high levels of dark pigment neuromelanin in dopaminergic neurons* +*Neuromelanin is directly biosynthesized from L-DOPA, precursor to dopamine, by tyrosine hydroxylase (TH)* + +-- + ## What causes dopaminergic neurons to die? -* Most cases are late-adult onset without a clear inheritance pattern. -* Small fraction are familial. -* α− Synuclein a synaptic protein that when mutated can lead to aggregation and cause the formation of Lewy bodies. Autosomal dominant mutations. -* Aggregates may spread from neuron to neuron. -* Two other autosomal recessive mutations Pink1 and Parkin block mitochondria function in dopaminergic neurons-conserved from fly to humans. +* Most cases are late-adult onset without a clear inheritance pattern +* Small fraction are familial +* α−synuclein a synaptic protein that when mutated can lead to aggregation and cause the formation of Lewy bodies. Autosomal dominant mutations +* Aggregates may spread from neuron to neuron +* Two other autosomal recessive mutations Pink1 and Parkin block mitochondria function in dopaminergic neurons-conserved from fly to humans Note: - - [from https://en.wikipedia.org/wiki/Parkinson%27s_disease](https://en.wikipedia.org/wiki/Parkinson%27s_disease) -mostly idiopathic, having no known cause >These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[7][37] In most cases, people with these mutations will develop PD. - - - - Models: mptp, insecticide rotenone, herbicide paraquat and the fungicide maneb. - - >proportion in a population at a given time is about 0.3% in industrialized countries. PD is more common in the elderly and rates rises from 1% in those over 60 years of age to 4% of the population over 80 - - alzheimers: [http://www.alz.org/facts/](http://www.alz.org/facts/) @@ -697,35 +473,34 @@ alzheimers: 6.4% dementia over 60 & 4.4% with AD over 60 - - ---- - + --- ## Treatments for Parkinson’s -* Dopamine can’t cross the blood brain barrier but L-dopa can. Stops working after a few years. -* Deep brain stimulation– bypass the circuit by inhibiting the the STN output. -* Cell replacement therapy– implant dopamine making neurons into the striatum. +* Dopamine can’t cross the blood brain barrier but L-DOPA can +* Deep brain stimulation +* Cell replacement therapy– implant dopamine making neurons into the striatum + +
Neuroscience 5e Fig. 6.10
+ +Note: + +*deep brain stimulation– bypass the circuit by inhibiting the STN output* [http://www.youtube.com/watch?v=mO3C6iTpSGo](http://www.youtube.com/watch?v=mO3C6iTpSGo) @@ -733,137 +508,139 @@ Note: [https://www.youtube.com/watch?v=JAz-prw_W2A](https://www.youtube.com/watch?v=JAz-prw_W2A) -
- -Note: [from: http://www.ncbi.nlm.nih.gov/books/NBK28180/](http://www.ncbi.nlm.nih.gov/books/NBK28180/) >Neutral l-amino acids have various rates of movement into the brain [13,14]. Phenylalanine, leucine, tyrosine, isoleucine, valine, tryptophan, methionine, histidine and l-dihydroxy- phenylalanine (l-DOPA) may enter as rapidly as glucose. These essential amino acids cannot be synthesized by the brain and, therefore, must be supplied from protein breakdown and diet (see Chap. 33) - - - - L-DOPA is transported across the blood brain barrier by LAT-1 (L or Large amino acid transporter). Dopamine is too polar to be lipid soluble and has no specific transporter - - non-polar: symmetric distribution of charge. - - - - --- ## Huntington’s disease -One of the most common inherited neurological disease. +* One of the most common inherited neurological diseases +* Progressive deterioration of the caudate and putamen that project to the GP externa (indirect pathway) +* Leads to a movement disorder consisting of rapid jerky motions with no clear purpose -Progressive deterioration of the caudate and putamen that project to the GP external, the head of the indirect pathway. - -Leads to a movement disorder consisting of rapid jerky motions with no clear purpose. - -
+
Neuroscience 5e Fig. 18.9
Note: +* George Huntington, physician long island 1872 +* 1 in 10000 people will have Huntington's disease in the US +* death in 10-20 yrs +* autosomal dominant inheritance, chromosome 4. Gene called Huntingtin +* if disease begins in childhood rigidity, seizures, dementia, and rapid progressive course can ensue +* atrophy of striatum is pronounced. Some associated degeneration of frontal and temporal cortices - ---- - -## Huntington’s Disease - - - - - - - - - - - - - - - - - - - - - -Note: - - - ---- - -## Summary explanation of hypokinetic and hyperkinetic disorders - -
- -Note: - - - ---- +-- ## Huntington’s disease -* Dominantly inherited– strikes around midlife. -* Patients develop depression, mood swings, and abnormal movements (striatum). -* Caused by alterations in a single gene that encodes the huntingtin protein. -* Huntingtin protein has an expansion of a CAG trinucleotide repeat, resulting in an extended polyglutamine (poly Q) repeat. Leads to aggregation of proteins and cell death. +* Dominantly inherited– strikes around midlife +* Patients develop depression, mood swings, and abnormal movements (striatum) +* Caused by alterations in a single gene that encodes the huntingtin protein +* Huntingtin protein has an expansion of a CAG trinucleotide repeat, resulting in an extended polyglutamine repeat. Leads to aggregation of proteins and cell death Note: +15-34 CAG DNA repeats normally, 42-66 in Huntingtin's disease resulting in an unstable triplet repeat in coding region of gene. Polyglutamine - ---- +-- ## The huntingtin protein has expanded glutamine repeats in the diseased state -
+
Note: +TODO: img src unknown +--- + +## Hypokinetic and hyperkinetic disorders summary + +
+
+ +* Parkinson's– hypokinetic disorder. More tonic inhibition of thalamus and decreased excitation of frontal cortex +* Huntington's– hyperkinetic disorder. Less tonic inhibition of thalamus and more excitation of frontal cortex + +
+ +
Neuroscience 5e Fig. 18.10
+
Neuroscience 5e Fig. 18.10
+ +Note: + +Parkinson's– hypokinetic disorder. More tonic inhibition of thalamus and decreased excitation of frontal cortex. + +Huntington's– hyperkinetic disorder. Less tonic inhibition of thalamus and more excitation of frontal cortex. + +-- + +## Movement disorders + +
Movement disorders
+ +Note: + +schizophrenia: +https://www.youtube.com/watch?v=OjM9Gl_MLyQ --- ## Non-motor loops of the basal ganglia -* Basal ganglia are also involved in loops that modulate non-motor behaviors. -* Maybe work the same way to suppress outputs. -* A limbic loop that may regulate emotional behavior and motivation. +* Basal ganglia are also involved in loops that modulate non-motor behaviors +* Maybe work the same way to suppress outputs +* A limbic loop that may regulate emotional behavior and motivation * Tourette’s may be a problem with limbic loop (no longer have inhibitions about language?) -* Drugs of abuse affect dopamine release. -* Schizophrenia, may be due to aberrant activity in multiple loops resulting in hallucinations etc. +* Drugs of abuse affect dopamine release +* Schizophrenia, may be due to aberrant activity in limbic and prefrontal loops resulting in hallucinations disordered cognition Note: +* prefrontal loop may regulate initiation and termination of cognitive processes like planning, working memory, attention +* limbic loop could initiate and terminate emotional and motivated behavior, transitions from one mood state to another +* deterioration of cognitive and emotional function in Parkinson's and Huntington's disease may be result of disruptions to these non-motor loops +* antipsychotic drugs that act on dopaminergic receptors support hypothesis that schizophrenia involves disruption of basal ganglia non-motor loops +* drugs of abuse that affect dopamine neurotransmission + * methylphenidate, amphetamine, meth, cocaine as well as those of nicotine [#Volkow-2000] + +from [#Volkow-2000]: +>drug abusers have marked decreases in dopamine D2 receptors and in dopamine release. This decrease in dopamine function is associated with reduced regional activity in orbitofrontal cortex (involved in salience attribution; its disruption results in compulsive behaviors), cingulate gyrus (involved in inhibitory control; its disruption results in impulsivity) and dorsolateral prefrontal cortex (involved in executive function; its disruption results in impaired regulation of intentional actions) + +* obsessive-compulsive disorder, depression, chronic anxiety all could involve dysfunctions of the limbic loop +* nucleus accumbens is a component of the limbic loop in ventral division of striatum and implicated in addiction to drugs of abuse expression of addictive reward-seeking behavior + +[#Volkow-2000]: Volkow, N. D., Fowler, J. S., Wang, G. J., Baler, R., & Telang, F. (2009). Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology, 56(Suppl 1), 3–8. http://doi.org/10.1016/j.neuropharm.2008.05.022 + +-- + +## Tourette's example + +
Tourette's
+ +Note: + +schizophrenia: +https://www.youtube.com/watch?v=OjM9Gl_MLyQ --- ## Types of corticostriatal loops -[http://www.youtube.com/watch?v=jYRa-fpNonY](http://www.youtube.com/watch?v=jYRa-fpNonY) - -Neuroscience 5e Box 18D +
Neuroscience 5e Box 18D
-
- Note: Tourettes may be a disruption to non-motor corticostriatal loops. --- - ---- - diff --git a/2016-11-25-lecture18.md b/2016-11-25-lecture18.md new file mode 100644 index 0000000..84eed2c --- /dev/null +++ b/2016-11-25-lecture18.md @@ -0,0 +1,1248 @@ +## Emotions + +* We all share common emotions– happiness, anger, surprise, fear, sadness. +* Very subjective– same stimulus does not give same response in all people in all situations. +* Emotions are strongly tied to the visceral motor system. How we feel it. +* Also tied to somatic muscle responses– especially facial muscles. How we express it. +* Limbic system– brain areas especially important for emotions. How we think it. +* Affective disorders. What goes wrong with it. + + +Note: + +--- + +## Visceral (autonomic) motor system + +* Two main subdivisions– sympathetic and parasympathetic subsystems. +* Sympathetic mobilizes the body’s resources for dealing with challenges. Fight or flight response. +* Parasympathetic deals with energy storage. Calms the body. +* Major locus of control is the hypothalamus and brainstem areas. + +Note: + +Visceral + +: relating to deep inward feelings rather than intellect + +--- + +## Autonomic motor system + +Neuroscience 5e Fig. 21.1 + +
+ +Note: + +Sympathetic Fight or flight, preganglionc: in the intermediolateral column. Postganglionic: Sympathetic chain + +blood vessels in skin and gut contract, rerouting blood to muscles + +hairs stand on end, piloerection making us look more fearsome, bronchi dilate for incr oxygenation, heart rate accelerates. Sympathetic activity also stimulates adrenal medulla to relesase adrenaline and noradrenaline into the bloodstream to mobilize glucagon release from pancreas. + + + + + +Parasympathetic: Preganglionic is in the brainstem, Peripheral ganglia in DRG + + + + + +--- + +## Autonomic motor system + +
+ +Note: + + + +--- + +## Facial expression of emotion + +* Duchenne de Boulogne +* Facial muscle stimulation can create a variety of expressions recognizable as emotion. + +
+ +
+ +Note: + +Emotions can trigger facial muscles that can’t be done on purpose. + +--- + +## Facial expression of emotion + +* Two pathways to get to facial muscles that display emotion– voluntary and emotional pathways are separable + +Neuroscience 5e Box 29A + + + +
+ +
+ +Note: + +extrapyramidal system: is a neural network that is part of the motor system causing involuntary movements + + + +pyramidal pathways (corticospinal and some corticobulbar tracts) may directly innervate motor neurons of the spinal cord or brainstem + + + +extrapyramidal system centers on the modulation and regulation (indirect control) + + + + + +Extrapyramidal tracts are chiefly found in the reticular formation of the pons and medulla, and target neurons in the spinal cord involved in reflexes, locomotion, complex movements, and postural control + + + +paresis: muscle weakness + + + + + +--- + +## Expression of emotion + +
+ +Note: + +animals express emotion as well— + +--- + +## Hypothalamus as a coordinator of emotional behavior + +* Phillip Bard / Walter Hess +* Hypothalamus as a critical center for coordination of both the autonomic and somatic components of emotional behavior. +* Removed huge areas of the forebrain and noticed two basic types of behaviors. +* One class exhibited as if they were enraged. Angry behavior occurred spontaneously and included the usual autonomic correlates of anger. Increased blood pressure and heart rate, dilation of pupil, hair raising. Also contained somatic motor components such as arching the back and tail. Called Sham rage. +* Sham rage found to require the hypothalamus. +* Stimulation of discreet parts of hypothalamus could elicit different behaviors associated with anger. + +Note: + + + +--- + +## Hypothalamus as a coordinator of emotional behavior + +* Phillip Bard / Walter Hess, early 1900s. Conducted seminal studies that determined the hypothalamus is a critical center for coordination of both the autonomic and somatic components of emotional behavior. + +[http://www.youtube.com/watch?v=TtU77nHL-p4](http://www.youtube.com/watch?v=TtU77nHL-p4) + +Neuroscience 5e Fig. 29.1 + + + +
+ +Note: + +started by removing cerebral hemispheres of cats, when anesthesia wears off they acted as if enraged. Involved all the autonomic components of the sympathetic nervous system. Called sham rage because no obvious target. + + + +Sham rage: Angry behavior occurred spontaneously included autonomic correlates of anger. Increased blood pressure and heart rate, dilation of pupil, hair raising. Also contained somatic motor components such as arching the back and tail. + + + +Connection from ventral hypothalamus to midbrain needs to be present to elicit sham rage. + + + +Bard suggested that emotional behaviors are often directed towards self-preservation (point also made by Charles Darwin). + +--- + +## + +
+ +Note: + + + +--- + +## Affective attack expression + +* Sham Rage +* An affective attack expression +* Evoked by radio stimulation of medial hypothalamus + +“Because the cat does not direct its attack toward any target, we regard this as just a fragment of a normal attack” (Delgado, 1981) + +
+ +Note: + + + +--- + +## Affective attack expression + +* Sham Rage +* An affective attack expression +* Stimulation of medial hypothalamus + +Note: + + + +--- + +## General connectivity of emotions + +* Both a volitional (with deliberate action) and a non-volitional component. Are in separate pathways. Both pathways ultimately lead to motor pools that activate muscle contraction or smooth muscle/gland secretions. +* Lateral projections control specific movements or emotional behaviors, medial projections provide support for these behaviors. + +Note: + + + +--- + +## Descending systems that control somatic and visceral motor pathways in the expression of emotion + +Neuroscience 5e Fig. 29.2 + + + +
+ +Note: + + + +--- + +## How does your brain impinge on emotions? + +* Anatomists had shown that there was a subregion of the brain that formed a rim around the corpus callosum and the medial aspects of the cerebral hemispheres. +* Contains the hippocampus and cingulate gyrus. +* These areas found to form a circuit with other areas, including hypothalamus–amygdala, and parts of the thalamus. Together these areas make up the limbic system. + +Note: + + + +--- + +## The limbic system + +Neuroscience 5e Fig. 29.4 + + + +
+ +Note: + +The limbic system. + + + +Green is modern view of limbic system critical for processing emotion. Blue includes other areas of the traditional limbic system such as the hippocampus and mammillary bodies that are not considered critical to circuits for emotional processing. + + + + + +--- + +## Limbic system + +Limbic system + +Basal ganglia + +
+ +
+ +Note: + + + +--- + +## Limbic system + +Neuroscience 5e Fig. 29.4 + + + +
+ +Note: + + + + + +amgydala—> ventral basal ganglia —> mediodorsal nucleus of thalamus —> orbital and medial prefrontal cortex —> amygdala + +--- + +## Crude lesion studies + +* John Downer (London in 1950’s) removed the temporal lobes of monkeys and witnessed weird emotional behaviors. +* Unable to recognize objects, although not blind. (why?) +* Bizarre oral behaviors +* Hyperactivity and hypersexuality, making physical contact with virtually anything. +* No longer showed fear. Neither to humans or to snakes. +* Eventually the fear behaviors was narrowed down to a region called the amygdala. +* [Kluver-Bucy syndrome– a disease due to damage of temporal lobe and limbic system https://www.youtube.com/watch?v=7RDFRASiq4M](https://www.youtube.com/watch?v=7RDFRASiq4M) + +Note: + + + +--- + +## Amygdala + +* Latin for ‘almond’ + +
+ +
+ +
+ +Note: + + + +--- + +## Selective lesion studies + +* Cut out only 1 amygdala (remember there is one on each side of brain) at the same time as transecting the optic chiasm, corpus callosum and anterior commissure. +* Optic chiasm cut blocks contralateral retinal axons thus now each eye’s information goes to same-side visual cortex. +* Creates an animal with a single amygdala that had access only to visual inputs from the eye on the same side of the head. +* If shut eye that goes to intact amygdala animals showed no fear responses. If open eye that maps to intact amygdala then animal shows normal fear behaviors. Therefore the amygdala is required for fear behaviors. + +Note: + + + +--- + +## Visual field deficits resulting from damage along the primary visual pathway + +Black means blind + +Blue means see + +Neuroscience 5e Fig. 12.6 + +Blindness in R eye + +Bitemporal hemianopsia + +L homonymous hemianopsia + +Upper quadrant hemianopsia + +Homonymous hemianopsia with macular sparing + +
+ +Note: + + + +--- + +## Insights on the role of the amygdala in appraising emotions from patient S.M. + +S. M. + +Neuroscience 5e Box 29d + + + +
+ +Note: + +patient SM has rare autosomal recessive condition called Urbach-Wiethe disease. Disorder of bilateral calcification an atrophy of anterior-medial temporal lobes. Both amygdalas are extensively damaged. Little to no injury of the hippocampus. + + + +She has no motor or sensory or intelligence or memory or language impairment. However she can’t recognize the emotion of fear in photographs. Furthermore, she exhibits little fear herself (to dangerous animals, scary houses, films, etc). + + + +--- + +## Insights on the role of the amygdala in appraising emotions from patient S.M. + +Adolphs et al. 1995 + + + +
+ +
+ +Note: + + + +--- + +## Adolphs et al., 1995 + +* Subject with bilateral amygdala lesions was asked to draw facial expressions of emotions. + +
+ +Note: + + + +--- + +## Amygdala: aggression + +* Among 603 operations for control of untreatable aggressiveness— +* there were 481 cases with bilateral amygdalotomies and 122 cases with mostly secondary posteromedian hypothalamotomies have been performed. Initially excellent or moderate improvement was achieved in 76%. After a follow-up of more than three years this figure only slightly decreased to 70%. The group of patients who did not positively respond (30%) needs further study to discover the reasons for failure. + +Note: + + + +--- + +## Fear conditioning + +* Pair a normally neutral stimulus with an inherently aversive one. Over time the animal will show behaviors to the neutral stimulus similar to that when given the aversive one. The animal learns to attach new meaning to a stimulus. +* Can use this assay to determine what areas of the brain are required for the learned behavior. + +Note: + + + +--- + +## Classic experiments demonstrating fear conditioning in an infant + +A white rat presented to an infant does not innately elicit fear, but pairing the rat with an aversive noise, produces crying and attempts to crawl away, even when the rat was presented without the noise. + +
+ +Note: + +Classic experiments from Watson and Rayner demonstrating fear conditioning in an infant + + + +As early as the 1920s, fear conditioning was demonstrated in infants. A white rat presented to an infant does not innately elicit fear, but pairing the rat with an aversive noise, produces crying and attempts to crawl away, even when the rat was presented without the noise. + + + +--- + +## Fear conditioning in rats + +Principals of Neural Science, Kandel, Schwarz, Jessel Fig. 50.07 + + + +
+ +Note: + + + +--- + +## Pathways involved in fear conditioning + +Neuroscience 5e Fig. 29.5 + + + +
+ +Note: + + + +--- + +## Amygdala: fear conditioning + +Sensory input + +Motor output + +Sensory input + +
+ +
+ +Note: + +CE – central nucleus, LA lateral Nucleus + + + +CG– central gray or PAG (periaqueductal gray). Primary control center for descending pain modulation. Enkephalin releasing neurons that project to raphe nuclei (and 5-HT in turn excites inhibitory interneurons in the spinal cord dorsal horn). Role in analgesia and defensive behavior. Responsible for the ‘freezing’ behavior of conditioned fear, the arresting of somatomotor activity. + + + +LH– lateral hypothalamus. Contains orexinergic neurons. Projects widely throughout nervous system. Promotes feeding behavior, arousal, reduces pain perception, regulates body temperature, digestive functions and blood pressure. Glutamate, endocannabinoids (anandamide), and orexin neuropeptides are main neurotransmitters in orexin neurons. Robust projections to posterior hypothalamus, tuberomammillary nucleus (histamine projection nucleus in posterior hypothalamus. Sole source of histamine pathways in human), arcuate nucleus (neuroendocrine neurons in mediobasal hypothalamus, prolactin, GHRH, ghrelin, neuropeptide-Y), paraventricular hypothalamic nucleus. + + + +PVN– paraventricular nucleus of hypothalamus. Contains groups of neurons activated by stressful or other physiological changes. Release oxytocin or vasopressin into circulation through terminals in the pituitary. + + + +--- + +## Long term potentiation (LTP) in the amygdala + +Synapse strengthened + +Synapse strengthened + +Synapse strengthened + +Synapse not strengthened + +Neuroscience 5e Fig. 8.9 + + + +
+ +Note: + + + +--- + +## NMDA receptor opening leads to strengthening of synapses + +
+ +Note: + + + +--- + +## Insertion of more AMPA receptors in synapse + +Neuroscience 5e Fig. 8.13 + + + +
+ +Note: + + + +--- + +## Spine growth, more synapses between neurons + +Neuroscience 5e Fig. 8.15 + + + +
+ +Note: + + + +--- + +## Physiological pathways for amygdala mediated fear conditioning + +
+ +Note: + + + +--- + +## Model for associative learning in the amygdala + +Neuroscience 5e Fig. 29.6 + + + +
+ +Note: + + + +--- + +## Model for the awareness of emotional feelings + +Neuroscience 5e Fig. 29.7 + + + +
+ +Note: + + + +--- + +## Emotions are lateralized + +* Right hemisphere is especially important for the expression and comprehension of the affective aspects of speech (emotional sides of language). +* People with lesions on the right side equivalent of Broca’s area speak in monotones. Unable to change tone to relay things like anger. +* Mood. Left side more associated with positive emotions and the right side more associated with negative emotions. +* Depression often associated with left side damage, right side damage leads to undue optimism. + +Note: + + + +--- + +## Mood disorders– depression + +* Can be unipolar or bipolar. +* Unipolar depression affects 5% of world’s population. 8 million Americans at any given time. +* Average age of onset 28 years. More common in women than men. +* Bipolar disorders– have a manic phase. 1% of people have it at some point during lifetime. Affects men and women equally. +* Account for a large fraction of suicides. + +Note: + + + +--- + +## Treatments for depression + +* Iproniazid- inhibits monoamine oxidase, increases monoamine concentration in synaptic terminals. +* Imiprmine and fluoxetine (Prozac), inhibit monoamine transporters. Prozac selectively inhibits serotonin reuptake, selective serotonin reuptake inhibitors) + +Note: + + + +--- + +## In vivo assay for inhibition of reuptake + +
+ +Note: + + + +--- + +## Anxiety disorders + +* Most common types of psychiatric disorders, include anxiety, phobias, panic disorders, obsessive-compulsive disorder. +* Often associated with fatigue, muscle tension, and sleep disturbance. 5% of people report some type of general anxiety disorder. +* Barbiturates– reduce anxiety but also are potent sedatives. Overdose is lethal. +* Benzodiazepines– reduce anxiety without as much sedation. Harder to overdose on benzodiazepines. +* Both drugs bind to the ionotropic GABA receptors and enhance GABA transmission. + +Note: + + + +--- + +## Benzodiazepine mechanism of action + +* Benzodiazepines increase the affinity of the receptor for GABA +* Barbituates can activate the GABA receptor independent of GABA + +
+ +Note: + +Act at the level at the interface of the alpha and gamma subunits. Different neurons express different gamma subunits. Six different genes for the alpha subunit. Benzodiazepines only can interact with the a1,a2, and a5 subunits, have a conserved histidine. + +--- + +## Drug abuse and addiction + +* Emotional processing in the limbic system signals the presence or prospect for reward and punishment, and activates programs to procure rewards and avoid punishment. +* Most known drugs (heroin, cocaine, ethanol, opiates, marijuana, nicotine, amphetamines) act on the limbic circuitry. +* Most act by altering dopamine circuits that go through the basal ganglia. + +Note: + + + +--- + +## Functional and anatomical organization of the limbic loop through the basal ganglia + +* Nucleus accumbens– contains MSNs +* Ventral tegmental area (VTA)– releases dopamine + +Nucleus accumbens + +Neuroscience 5e Fig. 29.10 + + + + + +
+ +Note: + +Much like the direct pathway. Inputs from different parts of cortex, including amygdala. + + + +to MSNs in ventral striatum the nucleus accumbens. These gabaergic projections then inhibit inhibitory projections in the in the ventral globus pallidus called the ventral pallidum. So there is a disinhibitory effect, much as we discussed before for other basal ganglia loops. + + + + + +--- + +## + +* + +Dopamine Pathways + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +Functions + +reward (motivation) + +pleasure,euphoria + +motor function + + (fine tuning) + +compulsion + +perserveration + +decision making + +Serotonin Pathways + +Functions + +mood + +memory + + processing + +sleep + +cognition + + + + + +nucleus + +accumbens + +hippocampus + +striatum + +frontal + +cortex + +substantia + +nigra/VTA + +raphe + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+ +Note: + + + +--- + +## Title Text + +[http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation06-03NeurotransmitterPathwaysDopamine.mov](http://courses.pbsci.ucsc.edu/mcdb/bio125/Animation06-03NeurotransmitterPathwaysDopamine.mov) + +
+ +Note: + + + +--- + +## Changes in the activity of dopamine neurons in the VTA during stimulus–reward learning + +Neuroscience 5e Fig. 29.12 + + + +
+ +Note: + +The VTA signals the occurrence of a reward relative to its prediction + +--- + +## Stimulation of reward pathway is incredibly powerful + +* Self stimulation experiments have demonstrated that rats will bar press for stimulation of the VTA or NAc +* Olds & Milner, 1954, J Comp Physiol Psychol, 47 +* This behavior can be blocked by cutting the pathway from the VTA or by administering dopamine antagonists. + +[http://www.youtube.com/watch?v=aNXhyPj-RsM](http://www.youtube.com/watch?v=aNXhyPj-RsM) + +
+ +Note: + + + +--- + +## + +* + +* 1) Mesolimbic (dopamine pathway) +* - Neurons from ventral tegmental area (VTA) to nucleus accumbens (major neurotransmitter: dopamine) +* - A critical pathway for drug addiction +* + +* 2) Amygdala: +* - help to assess whether an experience is pleasurable or aversive +* - and whether it should be repeated or avoided to forge connections between an experience and other cues +* + +* 3) Hippocampus: +* - recording the memories of an experience +* +* 4) Frontal regions: +* - coordinate and process all this information and determine the ultimate +* behavior of the individual. +* + +* 5) VTA– nucleus accumbens pathway +* - acts as a rheostat of reward: it tells the other brain centers how rewarding an +* activity is. The more rewarding an activity is deemed, the more likely the organism is to remember it well and repeat it + +Key components of reward circuits + +Note: + + + +--- + +## Addictive drugs hijack the brain’s reward system by enhancing the action of VTA dopamine neurons + +* Drug addiction: compulsive drug use despite long-term negative consequences. +* All drugs of abuse increase dopamine concentration at the output targets of the ventral tegmental area. +* Nucleus accumbens– processes reward information. +* Prefrontal cortex– goal selection and decision making. + +Note: + + + +--- + +## Circuits involved in drugs of abuse + +* Nicotine enhances input onto VTA by presynaptic excitation +* Opioids, benzodiazepines, and cannabinoids act by hyperpolarizing GABAergic neurons +* Ethanol boosts dopamine concentrations– mechanism unknown +* Cocaine blocks dopamine reuptake via the plasma membrane dopamine transporter (DAT) +* Ecstasy causes dopamine release in vesicle independent manner, inhibits +* Dopamine degradation and increases dopamine biosynthesis. + +Note: + +Specifically, studies in primates and rodents have shown that many VTA dopamine neurons encode reward prediction errors. This error signal is hypothesized to direct synaptic plasticity in target neurons in the nucleus accumbens and prefrontal cortex for reinforcement-based learning. If VTA dopamine neurons signal a reward, the action or behavior that immediately preceded the reward is reinforced through dopamine modulation of downstream circuits (see Figure 10–44). Drugs of abuse bypass natural signals that activate these dopamine neurons, thus dissociating the reward system from its natural stimuli. Specifically, by increasing dopamine concentration at dopamine neurons’ presynaptic terminals, drug consumption mimics dopamine neuron activation; this reinforces the preceding actions, include drug consumption itself. Thus, addictive drugs hijack the brain’s reward system and exploit mechanisms that otherwise regulate learning and motivational + +--- + +## Drugs of abuse act on endogenous neurotransmitter receptors and transporters + +Inhibits 5-HT transporters and VMAT. Increased + + + +DA, 5-HT, NA in synaptic cleft. + +Note: + + + +Cocaine + + + +DAT: dopamine transporter, extracellular + +NET: NA transporter, extracellular + +MAO: monoamine oxidase, intracellular. + +* : Catalyzes oxidation of monoamines (serotonin, melatonin, norepinephrine, epinephrine (MAO-A) and dopamine, tyramine, tryptamine (MAO-A & MAO-B) +* : bound to outer membrane of mitochondria of most cell types in the body. + +VMAT2: vesicular monoamine transporter, intracellular + +: blocking VMAT2 can cause reverse transport direction (cytosol to synaptic cleft) for monoamine transporters. Particularly for MDMA and amphetamines + +: SLC18A2 gene + +: transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from cytosol into synaptic vesicles + + + +-MDMA enters monoamine neurons by acting as a monoamine transporter substrate (i.e., a substrate for DAT, NET, and SERT) + + + +--- + +## Circuits involved in drugs of abuse + +* Nicotine enhances input onto VTA by presynaptic excitation +* Opioids, benzodiazepines, and cannabinoids act by hyperpolarizing GABAergic neurons +* Ethanol boosts dopamine concentrations– mechanism unknown +* Cocaine blocks dopamine reuptake via the plasma membrane dopamine transporter (DAT) +* Ecstasy causes dopamine release in vesicle independent manner, inhibits +* Dopamine degradation and increases dopamine biosynthesis. + +
+ +Note: + +Specifically, studies in primates and rodents have shown that many VTA dopamine neurons encode reward prediction errors. This error signal is hypothesized to direct synaptic plasticity in target neurons in the nucleus accumbens and prefrontal cortex for reinforcement-based learning. If VTA dopamine neurons signal a reward, the action or behavior that immediately preceded the reward is reinforced through dopamine modulation of downstream circuits (see Figure 10–44). Drugs of abuse bypass natural signals that activate these dopamine neurons, thus dissociating the reward system from its natural stimuli. Specifically, by increasing dopamine concentration at dopamine neurons’ presynaptic terminals, drug consumption mimics dopamine neuron activation; this reinforces the preceding actions, include drug consumption itself. Thus, addictive drugs hijack the brain’s reward system and exploit mechanisms that otherwise regulate learning and motivational + +--- + +## Drugs of abuse affect dopamine projections from the VTA to the nucleus accumbens + +
+ +Note: + + + + + +Exposure to drugs of abuse causes long-lasting enhancement of excitatory input to VTA dopamine neurons, increasing AMPA/NMDA receptor ratio at these synapses. + +--- + +## Exposure to drugs of abuse causes long-lasting enhancement of excitatory input to VTA dopamine neurons + +
+ +Note: + + + +--- + +## Long-term changes in the brain as a result of abuse + +* Decreases in CREB transcription factor in NAc (and extended amygdala) +* Decreases in metabolism in orbito frontal cortex (OFC) +* Decreases in dopamine D2 receptor binding + +Volkow et al. + +Synapse 14 (2), 1993, pp. 169-177. + +Striatum: caudate, putamen + +nucleus accumbens + + + +
+ +Note: + + + +--- + +## Schizophrenia + +* 1% of general population +* Onset during adolescence– hallucinations, delusions, and paranoia. Positive symptoms +* Social withdrawal, lack of motivation, cognitive impairment- Negative symptoms. +* Chlorpromazine and reserpine are drugs that alleviate positive symptoms, with side effects. +* Reserpine interferes with metabolism of all three monoamine neurotransmitters– dopamine, norepinephrine and serotonin by inhibiting a vesicular monoamine transporter (VMAT) effectively depletes the levels of these neurotransmitters. +* Chlorpromazine blocks D2 dopamine receptors. + +Note: + + + +--- + +## VMAT is a target of anti-psychotics + +
+ +Note: + + + +--- + +## Candidate genes associated with psychiatric disorders + +* Schizophrenia and bipolar disorder are heritable (80%) +* Depression and anxiety disorders is lower (30%). +* No simple Mendelian inheritance pattern has been shown but many genes have been implicated to be risk factors. + +
+ +Note: + +Table 11-2 Selected candidate genes associated with psychiatric disorders. + + + +--- + +--- + diff --git a/2016-11-25-methods2.md b/2016-11-25-methods2.md new file mode 100644 index 0000000..77bdc97 --- /dev/null +++ b/2016-11-25-methods2.md @@ -0,0 +1,2712 @@ +## Title Text + +* C. elegans neuronal network (279 out of 302 total neurons) + +* Determined through tracing and electron microscopy + +* red: sensory neurons, blue: interneurons, green: motor neurons + +* 6393 chemical synapses, 890 electrical junctions, and 1410 neuromuscular junctions + +Anatomical connectivity + +White et al, Phil Trans R Soc Lond B 1986 + +[http://www.wormatlas.org/neuronalwiring.html](http://www.wormatlas.org/neuronalwiring.html) + +
+ +
+ +Note: + + + + + + + + + + + + + +Wiring diagram of C. elegans (302 neurons total, 279 neurons shown here. 20 pharyngeal (of or relating to the pharynx) nervous system neurons not shown as well as 3 that do not make synapses with other neurons) + + + +red: sensory neurons + +blue: interneurons + +green: motor neurons + + + +number of possible node pairs is N*(N-1)/2 + + + +for c. elegans: > (302*301)/2 + +[1] 45451 + + + +> (279*278)/2 + +[1] 38781 + + + +6393 chemical synapses, 890 electrical junctions, and 1410 neuromuscular junctions + + + + + +horizontal axis represents closeness of connectivity (spring embedded graph layout) + +vertical aix represents signal flow from top to bottom + + + +from D. Chklovskii. White et al, Phil Trans R Soc Lond B 1986 + +--- + +## Genome size does not correlate with nervous system complexity + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +100,000,000,000 + +71,000,000 + +302 + +10,000,000 + +250,000 + +Number of + +neurons in whole nervous system + +
+ +Note: + +Number of genes is not related to nervous system complexity or size. The nematode c. elegans has just 302 neurons, and yet its genome contains virtually as many genes as a humans. An african elephant brain weighs 3 times more than a human brain and has 3 times the number of neurons. + + + +The largest brains are those of sperm whales, weighing about 8 kg (18 lb). An elephant's brain weighs just over 5 kg (11 lb), a bottlenose dolphin's 1.5 to 1.7 kg (3.3 to 3.7 lb), whereas a human brain is around 1.3 to 1.5 kg (2.9 to 3.3 lb). Brain size tends to vary according to body size. + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Investigating gene function + +Principles of Neurobiology, Garland Science Fig. 13-4 + +
+ +Note: + +Forward and reverse genetics. + + + +forward genetics, researchers start by observing an altered trait (phenotype) to id. the gene responsible for causing the phenotype of interest. + + + +in reverse genetics, researchers start with a gene of interest and disrupt the gene function, examing the phenotypic consequences. + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Making mammalian genetic models + +Principles of Neurobiology, Garland Science Fig. 13-6 + +
+ +Note: + +Making fancy mice. + +--- + +## Title Text + +* CRISPR/Cas9 system for faster genetic engineering + +Targeted editing of the genome + +Principles of Neurobiology, Garland Science Fig. 13-8 + +
+ +Note: + +crispr-cas9 system. + +crispr: clustered reguarly interspaced short palindromic repeat + +cas: crispr associated + + + +any eukaryotic dna that contains a PAM sequence can be a target. + + + +PAM sequence: protospacer associated motif, usually two or three nucleotides. Occurs frequently. + +* -canonical PAM is the sequence 5'-NGG-3' where "N" is any nucleobase followed by two guanine ("G") nucleobases + +* -Guide RNAs (gRNAs) can transport Cas9 to anywhere in the genome for gene editing, but no editing can occur at any site other than one at which Cas9 recognizes PAM. + + + +A guide RNA that contains sequences complementary to a piece of DNA from the target gene of interest brings the Cas9 enzyme to the target site on the chromosome through DNA-RNA base pairing (purple and red) + + + +Two nuclease domains of Cas9 create a double strand break in the genomic DNA. The double strand break can be repaired by the nonhomologous end joining system, through which small deletions or insertions may be created at the repair site. + + + +The ds break can also be repaird by the homologous recombination system with a donor DNA as a template, through which specific modifications such as insertion of a transgene can result. + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Timeline of genome sequencing advances + +Principles of Neurobiology, Garland Science Fig. 13-7 + +
+ +Note: + +timeline of selected milestones. Graph show exponential growth of sequencing technology in 10 yrs since draft of human sequences first published. + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Traditional anatomical methods for determining cortical areas + +Principles of Neurobiology, Garland Science Fig. 13-18 + +
+ +Note: + +Nissl stain and cortical area divisions. Border of V1 and V2. Adapted from Brodmann K (1909). + + + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Confocal and light sheet fluorescence microscopy + +Principles of Neurobiology, Garland Science Fig. 13-19 + +
+ +Note: + +confocal is on left. light sheet microscopy on the right. + + + +Confocal microscopy uses a small pinhole before the detector to allow emitted fluorescence from only the focal plane. + + + +In light sheet microscopy, illumination is proved from the side to produce a thin sheet of excitation light. + + + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Making brain tissue transparent for better microscopic imaging + +Principles of Neurobiology, Garland Science Fig. 13-20 + +
+ +Note: + +clarity based tissue clearing for fluorescene imaging. + + + +Intact tissue is fixed in prescence of hydrogel monomers that covalently link DNA RNA, and proteins into a mesh during subsequent polymerization. Lipids (which are a major cause of opacity for fluorescence imaging) are not covalently linked and are removed during subsequent clearing process by passive diffusion or electrophoresis in presence of detergent. Tissue is then transparent for better and deeper imaging. This example is from a Thy1-gfp transgenic mouse imaged with a confocal microscope. Shows neocortex, hippocampus, and thalamus. + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Injecting intracellular dyes to trace axonal projections + +Principles of Neurobiology, Garland Science Fig. 13-21 + +
+ +Note: + +Intracellular dye filling to trace axonal projections of a single neuron. Rat posterior piriform cortex pyramidal neuron. Injected in vivo followed by several days. Johnson et al., J Neurosci 2000. + + + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Super-resolution fluorescence microscopy + +Principles of Neurobiology, Garland Science Fig. 13-25 + +
+ +Note: + +Mapping synaptic protein organization with super res fluorescence microscopy. + + + +double labeling with basson (presynaptic scaffold protein, red) and postsynaptic scaffold protein (homer1, green) in mouse olfactory bulb glomerular layer. + + + +Imaged using stochastic optical reconstruction microscopy (STORM), a super resolution technique. Gets you beyond the diffraction limit for light microscopy, typically 100-150 nm with the highest resolution objectives and shortest wavelengths of visible light. + + + +Third image is higher magnification view. + + + +Right shows distribution of different antibody, STORM imaging resolved proteins around the synaptic cleft. + + + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Diffusion tensor imaging + +Principles of Neurobiology, Garland Science Fig. 13-26 + +[www.humanconnectomeproject.org](http://www.humanconnectomeproject.org) + +
+ +Note: + +Diffusion tensor imaging. + + + +sagittal view of human brain. + + + +Axon bundles running along medial-lateral axis are colored red. + +Those along anterior-posterior axis colored green. + +Axons running through brainstem colored blue. + + + +[www.humanconnectomeproject.org](http://www.humanconnectomeproject.org) + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Tracing of long distance connections in the mouse brain + +Principles of Neurobiology, Garland Science Fig. 13-27 + +[www.mouseconnectome.org](http://www.mouseconnectome.org) + +[connectivity.brain-map.org](http://connectivity.brain-map.org) + +
+ +Note: + +Mix of phytohemagglutnin (PHA-L, green) an anterograde trace and cholera toxin subunit b (CTb, magenta) a retrograde tracer injected into right insular cortex of a mouse brain. Stained in blue with fluorescent nissl stain. Projections from and to insular cortex. + + + +On right show adeno-assoc viruses expressing Cre-dependent GFP. Injected into motor cortex of mic expressing Cre recombinase in layer 6 or 2/3. Notice different projection patterns of neurons from these two layers in the rendered 3D views. + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Reconstruction of wiring diagram using serial EM + +Principles of Neurobiology, Garland Science Fig. 13-29 + +
+ +Note: + +serial electron microscopy to construct wiring diagrams. + + + +left is EM micrograph of drosophila medulla in optic lobe. + +High mag view shown at bottom showing presynaptic terminal with 4 contacts. + + + +Colored view showing segmented cellular elements in this image. + + + +Neurites reconstructed by registering and linking thousands of consecutive brain sections… from Takemura et al, Nature 2013 + + + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Using modified rabies virus to do monosynaptic tracing + +Principles of Neurobiology, Garland Science Fig. 13-30 + +
+ +Note: + +Gene encoding rabies virus glycoprotein is essential for viral recognition of host cells and for viral spread is replace with GFP in the rabies genome. This mutant rabies virus can no longer recognize and transduce normal mammalian neurons. + + + +Mutan rabies assembled in a cell line that helps assemble the virus with a coat protein from a different virus, the EnvA coat protein (blue). This makes it able to transfect mammalian cells that express the EnvA receptor TVA (cyan) from a transgene. + + + +A transgene that supplies the rabies glycoprotein is alos expressed in the starter cells. + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Principal methods for electrophysiology + +Principles of Neurobiology, Garland Science Fig. 13-31 + +
+ +Note: + +left is photo uncaging + +right is optogenetics + + + +parse out signal flow in the brain. + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Multielectrode arrays + +Principles of Neurobiology, Garland Science Fig. 13-33 + +
+ +Note: + +multielectrode arrays (like this 10x10 silicon based prototype) are widely used now for recordings from multiple cortical neurons simultaneously and for usages with neural prosthetics. from IEEE 1991 + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Laser scanning two-photon microscopy: imaging neurons in living mice + +Principles of Neurobiology, Garland Science Fig. 13-39 + +
+ +Note: + +two photon microscopy is non-linear magic. + + + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Chemical and genetically encoded calcium indicators + +Principles of Neurobiology, Garland Science Fig. 13-38 + + + +GCaMP6– genetic calcium indicator + +
+ +Note: + +chemical and genetically encoded calcium indicators. + + + +fura2 is a fluorophore with a calcium chelating site from calcium buffer EGTA. With low calcium, excitation at 380nm produces stronger fluorescence emission than excitation at 350 nm. Ratiometric imaging at 350/380 gives sensitive measure of [Ca2+] + + + +first genetic calcium reporter based on FRET (fluorescene resonance energy transfer). + + + +Gcamp. permutated gfp is restored to its native 3D structure with an associated increase in fluorescene after calcium triggered binding of the calmodulin binding peptide M13 to calmodulin. Fluorescent intensity thus gives readout of Ca2+. Single APs reliably induce fluorescent intensity changes in GCaMP6 in mouse visual cortical neurons in vivo. + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Recording neuronal activity in awake behaving mice + +Principles of Neurobiology, Garland Science Fig. 13-40 + +
+ +Note: + +Head fixed preparation on left during 2P imaging. The thirsty mouse can be trained to extend its tongue only when odor A, but not odor B is presented in order to receive a water reward. Motor cortical area controling tongue extension can be imaged during the learning process. + + + +Virtual reality preparation to test the neuronal correlates of memory dependent spatial navigation. Floating styrofoam ball that the mouse is trained to run on, head fixed with electrodes or 2P imaging. Screens providing continuous first person VR experience— in fact this was done by coding a VR environment based on the quake 2 game engine (if any of you have played the classic quake first person shooter games by id software). + + + +The right shows a miniaturized microscope weighing just over a gram that an adult mouse can carry on its head to image brain activity as it freely moves and navigates. + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Optical imaging of brain activity + +🎥 + +💭 + +1. Record brain activity patterns + + + + + + + +J. Ackman + +
+ +
+ +
+ +Note: + + + + + +use modern CMOS cameras and transgenic mice to image brain activity across both cerebral hemispheres simultaneously so that we are covering fields of view of 10-20mm. + + + +And this is now possible because we can use new transgenic mice that express a green fluorescent reporter protein that specifically exhibits increased fluorescence when neurons are electrically active. And what we do is to record population activity patterns transcranially with what we call functional mesoscale optical imaging. + +--- + +## Mesoscale imaging of neocortical dynamics + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +1 mm + +J. Ackman + +
+ +Note: + +And so here is the field of view of our preparation and what you’re looking at is the two cerebral cortical hemispheres of a young mouse being that was imaged transcranially. + + + +--- + +## Mesoscale imaging of neocortical dynamics + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +11x13mm FOV, postnatal day 5 (P5), SNAP25-GCaMP6 + + + +1000 µm + +J. Ackman + +
+ +
+ +
+ +Note: + +And if we want to know what population activity looks like across the developing cortex, here is your answer… + + + +that population activity in the developing cortex consists of discrete but overlapping domains of activation. So what you are seeing is the ongoing neuronal population activity throughout localized parts of the neocortex in a head stabilized, unanesthetised and resting young mouse. These movies are 10 min long recordings, that are acquired at a framerate of 5-10 fps, played back 6x here, and has been normalized to the mean fluorescence image for the entire 10 min long movie so that you are looking at changes in pixel intensity. This means you see neuronal activity show up as these bright blobs in the brain, as well as motion of the paws, hair, and whiskers of the animal within the field of view. + + + +We think much of this activity is spontaneous but some of it is self stimulated tactile responses because the animals often exhibit limb twitches just as you do when you’re drowsy or when you were in the womb. + + + +This technique is important because the functional organization —> of the mature brain is distributed across areas with different functions within and between hemispheres. + + + +Because this method is minimally invasive, requiring just retraction of the scalp and no local dye injections, this will be a technique of choice for large range of experiments including those requiring in vivo imaging in different behaving, unanesthetised mouse lines. + + + +And to illustrate the sensitivity of this cortical activity to general anesthesia, we can watch the following movie… + + + +--- + +## Optogenetics – a new technique for understanding brain function + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +[http://www.youtube.com/watch?v=I64X7vHSHOE](http://www.youtube.com/watch?v=I64X7vHSHOE) + +
+ +Note: + + + +--- + +## Title Text + +* Channelrhodpsin-2 (ChR2) from green algae is a cation channel gated by blue light + +* Allows more Na+ influx than K+ efflux causing depolarization + +Optogenetics for precise control of neuronal activity + +Principles of Neurobiology, Garland Science Fig. 13-45 + +[http://www.youtube.com/watch?v=I64X7vHSHOE](http://www.youtube.com/watch?v=I64X7vHSHOE) + +
+ +Note: + + + +--- + +## Title Text + +* Combining methods for read/write control— of the brain! + +Mapping connectivity by combining optical and electrophysiological methods + +Principles of Neurobiology, Garland Science Fig. 13-47 + +
+ +Note: + +left is photo uncaging + +right is optogenetics + + + +parse out signal flow in the brain. + +--- + +## Title Text + +* Multimodal sensory activation, focuses attention, object tracking and stereoscopic vision/depth perception, salience of object, defensive/self preservation, limbic loop, decision making, movement selection, proximal and distal motor pool recruitment, reflex activation— but all from a previously unexperienced activity! + +“I didn’t have time to think” + +2016-03-10 09:48:33 + +
+ +Note: + + + +--- + +## Title Text + +* 30 ms before reaching LGN. 60 ms to primary visual cortex. Color information slower (M cell vs P cell pathways). + +Response latency in macaque visual system + +2016-03-10 09:48:33 + +
+ +Note: + + + +--- + +## Title Text + +* cell body (soma)– metabolic center of the cell, contains the nucleus. + +* dendrites– receive incoming signals from other nerve cells + +* axon– carries signals to other neurons + +* axon hillock– initiates action potentials + +* synapse– site at which two neurons communicate + +* synaptic cleft– area between pre and post-synaptic cell + +Structures of a neuron + +2016-03-09 11:31:59 + +Note: + + + +--- + +## Neuron Processes: Action Potentials + +* Nerve impulse (action potential) + +* Neuron receives and sends signals + +* Generated at the initial segment of the axon + +* Conducted along the axon + +* Releases neurotransmitters at axon terminals + +* Neurotransmitters – excite or inhibit neurons + + + +
+ +Note: + + + +--- + +## Neurons communicate by electricity + +* Axons project great distances + +* Neurons do not touch each other directly. + +* Come in close proximity at the synapse + +* Use action potentials to transmit information + +* Action potential causes release of neurotransmitter that is received by post-synaptic cells. + +Note: + + + +--- + +## Ways to measure neural activity + +* Extracellular recording– an electrode is placed near a neuron. Measures action potentials. Useful for detecting patterns of activity. + +* Intracellular recording– an electrode is placed inside a neuron-can measure smaller graded potential changes. Useful for isolating responses to single inputs. + +* Voltage clamping– can make the membrane potential of a cell at a desired point and determine the current flow across the membrane. + +* Patch Clamping– can measure ion flow across a single channel. + +* fMRI– infer activity indirectly in a living brain based on brain oxygenation patterns + +Note: + + + +--- + +## Basic parts of the CNS + +* Spinal cord + +* Brain stem + +* medulla + +* pons + +* midbrain + +* Cerebellum + +* Forebrain + +* diencephalon + +* cerebral hemispheres + +
+ +Note: + +These are the basic parts of the CNS + +--- + +## Words used to describe locations in the CNS + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## General rules of spinal cord organization + +* Neurons and axons that process and relay sensory information (afferents) are in dorsal spinal cord. + +* Preganglionic visceral motor neurons (innervate glands) are found in the intermediate/lateral region. + +* Interneurons are in intermediate zone. + +* Motor neurons and axons are found in the ventral portion of the cord. + +* Distal muscles are innervated by lateral motor neurons. + +* Proximal muscles by medial motor neurons. + +Note: + + + +--- + +## Spinal cord tracts + +* Dorsal column– sensory signals travels up it to the brain. + +* Lateral columns– also called the cortico-spinal tracts. Take signals from brain and sends it to the muscles. + +* Ventral columns (sometimes called anterolateral column)– carry pain signals up and motor signals down. + +Note: + + + +--- + +## Spinal cord tracts + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Nissl stain (cell bodies) + +Myelin stain + +
+ +Note: + +Dorsal column-sensory info travels up to the brain. + +Lateral columns-also called the cortico-spinal tracts. Take info from brain and sends it to the muscles. + +Ventral columns (sometimes called anterolateral column)- carry pain info up and motor info down. + + + +--- + +## Brain stem + +* + +* Medulla– regulates blood pressure and respiration. + +* Ventral pons– pontine nuclei, relay signals from cortex to the cerebellum + +* Dorsal pons– respiration taste and sleep + +* Midbrain– auditory and visual systems, substantia nigra pars compact (dopaminergic neurons). Deteriorates in Parkinson’s disease. + +Note: + + + +--- + +## Diencephalon + +* Contains the thalamus and hypothalamus + +* Thalamus– “relay station to the cerebral cortex”- an essential link in the transfer of most sensory information from periphery to cerebral cortex. Also plays a role in filtering information from the periphery. + +* Hypothalamus– lies ventral to thalamus. Controls a variety of functions, growth, eating, drinking, maternal behavior by regulating hormonal secretions of the pituitary gland. Connects to virtually every part of brain. Important in initiating and maintaining behaviors that the organism finds rewarding + +Note: + +The diencephalon contains the… + +The thalamus can be generally thought of as the relay station to the cortex. + +The hypothalamus lies ventral to the thalamus and controls an array of important physiological functions such as feeding, fluid balance, and hormonal secretions of the endocrine system. + +--- + +## Cerebral Hemispheres + +* Largest portion of the human brain + +* Cerebral cortex– cognitive functioning + +* Hippocampus– memory + +* Basal ganglia– control of fine movement + +* Amygdala– social behavior and expression of emotion + +Note: + +Now let’s finally talk about highest order parts of teh central nervous system the cerebral hemispheres. + +The two cerebral hemispheres sit atop and surround the diencephalon and much of the brain stem. + +Seat of cognition, but it doesn't work alone! + + + +limbic system includes both the amygdala is the integrative center for emotions, emotional behavior, and motivation + +--- + +## Lobes of the cerebral hemispheres + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Primary motor cortex + +Primary somatosensory cortex + +
+ +Note: + + + +--- + +## Cortical neurons are organized into layers + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Neuronal signaling + +* Electrical signals of nerve cells + +* Voltage-dependent membrane permeability + +* Channels and transporters + +* Synaptic transmission + +* Neurotransmitters, receptors, and their effects + +* Molecular signaling within neurons + +Note: + +So, how do neurons convey information over long distances that results in information transfer to other neurons at synaptic connections? It through electrical signaling that neurons are able to generate and transmit information. And this electrical signaling is possible because of a combination of… + + + +- voltage-dependent membrane permeability + +* - which in turn requires special membrane proteins called ion channels and transporters + +- synaptic transmission + +* which in turn requires neurotransmitters, their membrane bound protein receptors and their resulting effects + +as well as general molecular signaling within neurons as any living cell might have + + + +--- + +## Types of electrical signals in neurons + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + +This figure shows these 3 types of neuronal signals. + + + +Here is a receptor potential in a pacinian corpuscle, which is a type of mechanosensory receptor on sensory nerve endings near the surface of your skin. + + + +Here is a synaptic potential recorded in a postsynaptic neuron. + + + +Here is an action potential in a motor neuron. Look as the y-axes here— the action potential has a much larger amplitude change than receptor or synaptic potentials. + + + + + +--- + +## Nernst equation + +* Statement of the equilibrium condition for a single ion species across a membrane that is permeable only to that ionic species: + +* + +* + +* Ex = equilibrium potential in mV + +* R = the gas constant (8.3 J mol-1 K-1) + +* T = absolute temperature (K) + +* F = faraday constant (9.6x104 J mol-1 V-1) + +* z = valence of the ion, including sign. + +* ln = natural log (base e) + +* [x]out concentration of an ion outside; [x]in inside + +* + +* RT/F can be a constant at room temperature to give a simplified equation: + +* + +
+ +
+ +Note: + +So I stated that the Nernst equation is how we can calculate the equilibrium potential for a cell membrane permeable to one type of ion. + + + +And here is the Nernst equation is: + +Where Ex is: + + + +Gas constant R equivalent to the Boltzmann constant but expressed in units of energy. The physical significance of R is work per degree per mole. R = 8.3144598 J mol−1 K−1 == R = work / amount x temperature. Relates the energy scale in physics to the temperature scale, when a mole of particles at the stated temperature is being considered. Joules/mol/K + + + +Faraday constant = magnitude of electric charge per mole of electrons = 96485.33289 C/mol. Expressed in C/mol or J/mol/V + + + +Temperature is: + +z is the valence of the ion in question + +ln is the natural logarithm which has the mathematical constant e or 2.718 as it’s base. + + + +Now many of the classical experiments recording membrane potential in squid axon or other preparations were conducted at room temperature, which is 20ºC or about 68ºF. + + + +Thus to make calculations simpler in the classic scientific papers (often from the 1930s and 1940s before computers) this equation for experiments carried out at room temperature is often simplified to the following of: + + + +which uses the base10 logarithm. Since —> + + + +ln(x) / log10(x) = 2.30 + +—> 2.30 * log10(x) = ln(x) + + + +R = 8.3 J/K*mol, T = 37ºC + 273ºC = 310 K, F = 9.6*10^4 J/mol*V + +E = + + + +log(7) / log10(7) + +R = 8.3 + +F = 9.6 * 10^4 + +T = 20+273 + +(R*T / F) * 1000 * 2.3 + +==>58.26427 + + + + + +--- + +## Title Text + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +K+ concentration gradient determines resting membrane potential + +why does it deviate from the line at low K+ concentrations? + +increasing extracellular K+ increases resting potential + +
+ +Note: + +So Hodgkin and Katz did this experiment, varying the extracellular K+ concentration while recording the squid axon membrane potential and found that increasing the Kout incr the resting membrane potential. + + + +They plotted resting membrane potential against the extracellular K+ concentration, shown in this red curve. + + + +If internal K+ is unchanged, a plot of membrane potential against the log of external K+ concentration would yield a straight line with slope of 58mV per tenfold change in external K+ concentration at RT. + + + +However it deviates from this expected relationship (shown by the black line), especially at lower K+ concentrations. Why is this? + + + +Because other ions, particularly Cl- and Na+, are also slightly permeable and the contribution of these other ions is more evident at low K+ concentrations. + + + +--- + +## Role of sodium in the generation of an action potential + +* Lowering Na+ decreases both the rate and the rise of an action potential + +
+ +Note: + +When Hodgkin and Katz did this low extracellular Na experiment, the AP had a smaller amplitude and also had a slower or longer timecourse so that the squid axon spiked at slower rate. + +--- + +## The action potential– summary + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + + + +Rising phase + +Overshoot phase + +Falling phase + +Undershoot phase + +
+ +Note: + +And this is just a overall summary of what we have been discussing + +--- + +## Electric current flow across a squid axon membrane + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +nothing (except for a capacitive transient) + +inward and + +outward currents + +
+ +
+ +Note: + +And so here are the results from this type of voltage clamp experiment. + + + +If you command that the cell membrane potential be hyperpolarized, you get very little or negligible current flowing across the membrane except for a very brief capacitive current that you always see in these voltage clamp experiments. + + + +This is because the cell membrane essentially acts as a parallel RC circuit where a resistor and a capacitor are connected in parallel and to a constant current source. Ion channels are resistors, lipid bilayer with the extracellular and intracellular environments act as capacitor, storing charge in the form of ions accumulating near the surface of the membrane. When a switch is turned on in an RC circuit current flows from the battery to the capacitor until the capacitor is charged to a voltage that is same as the battery. + + + +However when Hodgkin and Huxley depolarized the membrane, a transient inward current occurs followed by a slow outward current. + + + + + +* A capacitor (originally known as a condenser) is a passive two-terminal electrical component used to store electrical energy temporarily in an electric field. Consists of two parallel conductors. Lipid membrane with the inner and outer cellular environment acts as this. The membrane capacitance per unit areas is mostly constant at about 1 µF/cm2. + + + +* When the voltage is constant, the current through the capacitative pathway is zero because the capacitor has acquired the charge Q (coulombs) according to the relationship Q=CV. C is capacitance (farads) Ic is capacitive current. Ic = C(dV/dt) + +* as long as V is changing with time, there will be a current flowing towards the capacitor. + +* if V is constant in time, there is no capacitive current. + +* product of resistance and capacitance has the unit of time and is called the time constant. Time constant defines how quickly capacitors charge or discharge over time. + +* + +[http://nerve.bsd.uchicago.edu/med98c.htm](http://nerve.bsd.uchicago.edu/med98c.htm) + + + + + +--- + +## Current produced by membrane depolarizations at several different potentials + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +no inward current + + + +outward current + + + +inward current + + + + + + + + + + + + + + + + + +
+ +Note: + +This show several different voltage steps (with the brief capacitive current omitted for clarity) + + + +…Notice as we approach ENa the inward current disappears. + +--- + +## Speed of action potential conduction in unmyelinated versus myelinated axons + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Patch clamp + +* Allows one to look at currents flowing through a single channel. + +* Pipette with small opening makes a tight seal with the membrane. + +* Currents are amplified and measured + +* Can be adapted to do whole cell recordings, inside out recordings or outside out recordings. + +Note: + + + +--- + +## Measurements of ionic currents flowing through single Na+ channels + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Small inward currents + +Open at beginning of pulse + +Close quickly + +Neuroscience5e Fig. 4.1 + +
+ +Note: + +Patch a piece of membrane and block K currents. Do a bunch of short recordings while clamping the membrane at depolarized potential. e.g. here is 7 trials. Notice the amplitude is discrete— it is unitary. If you were recording from lots of… + + + +Transient channel opening in Na+ channels (inward current). + + + +--- + +## Measurements of ionic currents flowing through single K+ channels + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Early delay in opening + +Once open stay open + +Neuroscience5e Fig. 4.2 + +
+ +Note: + +Sustained channel opening in K+ channels (outward current). + +--- + +## Functional states of voltage-gated Na+ and K+ channels + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Neuroscience5e Fig. 4.3 + +
+ +Note: + +Shown here is a model of the functional states for these channels. Notice a few states for Na vs two for K. + +--- + +## 11 steps of synaptic transmission + +* Neurotransmitter is synthesized and packaged into vesicles. + +* An action potential invades the presynaptic terminal. + +* Depolarization causes opening of voltage-gated calcium channels. + +* There is an influx of Ca2+. 10-4 mM outside 10-7 mM inside. Rushes in fast. + +* Calcium causes vesicles to fuse with membrane. + +* Neurotransmitter is released into cleft. + +* Transmitter binds to receptors on postsynaptic cell + +* This opens or closes postsynaptic channels. + +* Postsynaptic current flows inside post-synaptic cell. + +* Removal of neurotransmitter by glia uptake or enzymatic degradation + +* Retrieval of membrane via endocytosis. + +Note: + + + +--- + +## Formal criteria that define a neurotransmitter + +* Must be present in the presynaptic neuron. + +* Must be released in response to a depolarization and be Ca2+ dependent. + +* Must have specific receptors localized on the post-synaptic cell. + +* Note: It does not have to function uniquely a neurotransmitter (it may have other functions). e.g. glutamate, glycine, ATP. + +Note: + + + +--- + +## Major categories of neurotransmitters + +* Small molecule neurotransmitters– amino acids, purines, biogenic amines. + +* Peptide neurotransmitters– 3-36 amino acid polypeptides, often derived from longer polypeptides. + +Note: + + + +--- + +## Acetylcholine + +* The neurotransmitter used at the neuromuscular junction. Also used at synapses in visceral motor system and at some CNS synapses– called cholinergic neurons. + +* Synthesized from acetyl CoA and choline by choline acetyl transferase (ChAT)– its presence is a good indication that the neuron is cholinergic. + +* Removed from synapse by acetylcholine esterase (AChE) has high activity can cleave 5000 molecules per second + +* Sarin “nerve gas” is a AChE inhibitor + +Note: + + + + + +ACh: skeletal muscle excitation vs release from vagus nerve that slows down heart beat (cardiac muscle)— + +* -Ligand gated channel that depolarizes skeletal muscle fibers vs g-protein coupled receptor that results in hyperpolarization of cardiomyocytes. + +* + +* + +--- + +## Glutamate + +* Most important transmitter for normal brain function. + +* Nearly all excitatory neurons in the CNS are glutamatergic. + +* Does not cross the blood brain barrier. + +* Glutamine is most common precursor glutaminase converts it to glutamate. + +* Retrieved from synapse by glutamate transporters in glia and neurons. Glia (astrocytes) turn glutamate to glutamine and spit it back out + +* Too much glutamate can kill the post-synaptic neuron (excitotoxicity). A major problem after damage due to stroke. + +Note: + +Most important neurotransmitter for normal brain function. Almost all excitatory neurons in CNS are glutamatergic. Half of all synapses estimated to use this transmitter. Glutamate is non-essential a.a. (by that I mean non-essential per dietary requirements) that does not cross the blood brain barrier. Synthesized inside neurons by local precursors. + + + + + +histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. + + + +Monosodium glutamate (MSG, also known as sodium glutamate) is the sodium salt of glutamic acid + + + + + +--- + +## GABA and glycine + +* Most inhibitory neurons use one or the other. + +* Inhibits the ability to fire action potentials. + +* GABA (gamma-aminobutyric acid) made from glutamate by glutamic acid decarboxylase (GAD), requires Vitamin B6 as cofactor. B6 deficiency can lead to loss of synaptic transmission. + +* Glycine– about 1/2 of neurons in spinal cord use glycine. + +* Both GABA and glycine are rapidly taken up by glia and neurons. + +* Hyperglycinemia– defect in glycine uptake and removal leading to severe mental retardation. + +Note: + +As many as a third of synapses in the brain use GABA as an inhibitory transmitter. Most commonly found in local circuit neurons. + + + + + + + +glycine encephalopathy: + +[http://ghr.nlm.nih.gov/condition/glycine-encephalopathy](http://ghr.nlm.nih.gov/condition/glycine-encephalopathy) + +>Glycine encephalopathy, which is also known as nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high levels of a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain, leading to serious medical problems. + + + + + + + + + + + +--- + +## Dopamine + +* Produced by the enzyme DOPA decarboxylase + +* Made by substantia nigra pars compacta (which connects to corpus striatum for coordination of body movements). + +* Does not cross the blood brain barrier, but levadopa (L-DOPA) does. + +* Parkinson’s treatments include L-DOPA plus degradation enzyme inhibitors + +* Cocaine inhibits uptake of dopamine (inhibits DAT) + +
+ +Note: + +Synthesized in cytoplasm of presynaptic terminals. + +Loaded into synaptic vesicles by vesicular monoamine transporter (VMAT). Dopamine in synaptic cleft is terminated by reuptake of dopamine into nerve terminals or glia cells by a Na-dependent dopamine cotransporter called DAT. Cocaine works by inhibiting DAT, increasing dopamine concentrations in synaptic cleft. + + + +Amphetamine also inhibits DAT as well as a transporter for norepinephrine + + + +Catabolized by monoamine oxidase and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT. Inhibitors of these enzymes are targets of some kinds of antidepressants (phenelzine and tranylcypromine) + + + +Acts throught GPCRs. D3 parallels that of other metabotropic receptors like mAChR. Subtypes act by activating or inhibiting adenylyl cyclase. + + + +Activation leads to complex behaviors. Antagonists can cause catalepsy (state where difficult to initiate voluntary movement). + + + + + +-L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. + +* -it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. + + + + + +Encephalitis lethargica, sleeping sickness, 40 yrs later Oliver Sacks in NYC treats them with L-DOPA + + + +Latinneostriatum + +Part of + +* Basal ganglia[1] + +* Reward system[2][3] + +Components + +* Ventral striatum[2][3][4 + +* Dorsal striatum[2][3][4] + + + +The corpus striatum, a macrostructure which contains the striatum, is composed of the entire striatum and the globus pallidus. The lenticular nucleus refers to the putamen together with the globus pallidus. + +--- + +## Neurotransmitter receptors + +* Embedded in the plasma membrane of post-synaptic cell. + +* Either are ion channels themselves (ionotropic, or ligand-gated ion channel) or interface with ion channels (metabotropic, or G-protein coupled receptors). + +* Ultimately, the binding of neurotransmitter causes opening of channels and ion flux. This can lead to depolarization or hyperpolarization of the membrane potential depending on the ion concentrations and the particular ion species flowing in or out. + +Note: + + + + + + + + + + + + + + + +Today we will dive a bit deeper into the structure and function of neurotransmitter receptors. + + + + + +--- + +## Hypothetical ion channel selectivities and the reversal potential + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + +So let’s imaging what the current-voltage relationships would look like for different channel selectivities. Remember the reversal potential is when there there is no net ion flux, so it 0 nA on all these graphs and if a channel is selective to only K, it would be equal to the Ek. + + + +If the channel was selective only to Na, than the Erev would be equal to ENa. Same for chloride. + + + +If the channel was a non-selective cation channel (passing both K and Na) than + + + + + + + + + +11Na, 12Mg, 17Cl, 19K, 20Ca + + + + + +--- + +## Na+ and K+ movements during EPCs and EPPs + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +-90 typical resting potential of a muscle + +depolarization + +hyperpolarization + +nothing + +Neuroscience 5e 5.20 + +
+ +Note: + +Even though these ionotropic channels opened by ACh are permeable to both Na and K, at the resting membrane potential the EPC is generated primarily by Na influx because of the reduced driving force on K since at Vrest the membrane potential is closer to Ek. + +--- + +## Summation of postsynaptic potentials + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Neuroscience 5e 5.22 + +
+ +
+ +Note: + + + +--- + +## Events from neurotransmitter release to postsynaptic excitation or inhibition + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Glutamate receptors + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## NMDA receptor currents require glycine and removal of Mg2+ block + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + + + + + +fig from: + +[http://www.bris.ac.uk/synaptic/info/glutamate.html](http://www.bris.ac.uk/synaptic/info/glutamate.html) + + + +--- + +## Effector pathways associated with G-protein coupled receptors + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +There are many types of alpha, beta, and gamma g-protein subunits allowing a specific and diverse range of downstream responses. + + + +This shows three examples of different heterotrimeric g proteins bound to 3 types of receptors with 3 different cellular responses. + + + + + +--- + +## Parallel processing of sensory information + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + +Totally fascinating to think out how all this works. Talk about which ones we will go over, common principles, all can get linked together. + +--- + +## Compare and contrast sensory systems + +* What are the peripheral receptors? What is their receptive field? What neurotransmitters are used? + +* How is the information translated into changes in cell potential? + +* What are the circuits, how do they get to the cortex? + +* What types of perception defects are associated with damage to different components of the system? + +Note: + + + +--- + +## Overall organization of neural structures that control movement + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Lower motor + +system + +State of muscle + +contraction/relaxation + +Execute + +movement + +Output + +system + +Upper motor + +system + +Gating + +Motor + +learning + +
+ +Note: + + + +--- + +## Motor pools + +* Retrograde labeling of muscles show that the cell bodies of motor neurons are found in ventral horn of the spinal cord. + +* Each motor neuron innervates muscle fibers within a single muscle. + +* All the motor neurons innervating a single muscle are grouped together in clusters called motor pools. + +* Motor pools are located with a slight spread along the A-P axis. + +* There is topography along medial-lateral axis of the spinal cord. Neurons that innervate axial musculature (trunk) are located medially, neurons that innervate distal muscles are located laterally. + +
+ +Note: + + + +--- + +## Types of motor neurons + +* α motor neurons– innervate the extrafusal muscle fibers, the striated muscle fibers that generate the forces needed for movement. + +* γ motor neurons– innervate specialized muscle fibers in the muscle spindles that are embedded within connective tissue in the muscle, known as intrafusal muscle fibers. These fibers are also innervated by sensory axons that send info to the brain and spinal cord about the length and tension of muscle. + +Note: + + + +--- + +## Types of motor units + +* Slow (S) motor unit– Small motor neurons innervate relatively few muscle fibers and generate small forces. They innervate small “red” muscle fibers that contract slowly but are relatively resistant to fatigue. These are rich in mitochondria and myoglobin, and are important for activities that require sustained muscular contraction such as posture. + +* Fast fatigable (FF) motor unit– Large motor neurons innervate larger, more powerful units. Larger α motor neurons innervate larger pale muscle fibers that generate more force, have sparse mitochondria and are easily fatigued. + +* Fast fatigue-resistant (FR) motor unit– are of intermediate size, not as fast as FF units but less fatigable. + +Note: + + + +--- + +## Recruitment of motor neurons to medial gastrocnemius (leg muscle) + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + +slow for standing + +FR for walking or running + +FF for sprinting, jumping + +--- + +## Comparison of the function of muscle spindles and Golgi tendon organs + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Comparison of the function of muscle spindles and Golgi tendon organs + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Overview of descending motor control + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Neuroscience 5e Fig. 17.1 + + + +
+ +Note: + +med ventral horn has lower motor neurosn for posteure balance and orienting movements of head and neck during shits of visual gaze. receipve descending input from the pathways orginating mainly in the brainstem, course through the anterior medial white matter of the spional cord and terminate bilaterally. + + + +lateral ventral horn contains lower motor neurons that mediate skilled voluntary movements of the distal extremities. Receive descending projection from the contralateral motor cortex via lateral division of the corticospinal tract. + + + + + +--- + +## The medial descending motor pathways + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + + + +
+ +Note: + + + +--- + +## Overview of descending motor control + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + +somatotopic organization of the ventral horn in the cervical enlargement. Locations of descending projections from the motor cortex in the lateral white matter and from the brainstem in the anterior-medial white matter are shown. + + + +--- + +## Section of pyramidal tracts in monkeys produces loss of independent digit control + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Intact (normal) + +After section of + +corticospinal fibers + +
+ +Note: + +corticalspinal, lateral dorsal input for control of distal/fine movements of the fingers. + +--- + +## Modulation of movement by the basal ganglia + +* Basal ganglia do not project directly to the spinal cord, instead they influence movements by regulating the activity of upper motor neurons. + +* The basal ganglia are a large set of nuclei that lie deep within the cerebral hemispheres. + +* Three main nuclei– caudate, putamen, and the globus pallidus. + +* Together with the substantia nigra and the subthalamic nucleus make a loop that links most areas of the cortex with upper motor neurons. + +* These neurons are required for the normal course of voluntary movements. Supervise motor movements. + +Note: + + + +--- + +## Direct and indirect pathways through the basal ganglia + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Dopamine excites the direct and inhibits the indirect pathway + + + +Neuroscience 5e Fig. 18.7 + + + +
+ +Note: + + + +--- + +## Hemiballismus: violent involuntary movements of the limbs + +* Defects in the subthalamic nucleus of the contralateral side of the movements + + + + + + + + + + + + + + + + + +
+ +
+ +Note: + + + +--- + +## Summary explanation of hypokinetic and hyperkinetic disorders + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Summary explanation of hypokinetic and hyperkinetic disorders + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +
+ +Note: + + + +--- + +## Descending systems that control somatic and visceral motor pathways in the expression of emotion + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Neuroscience 5e Fig. 29.2 + + + +
+ +Note: + + + +--- + +## Pathways involved in fear conditioning + +* Body Level One + +* Body Level Two + +* Body Level Three + +* Body Level Four + +* Body Level Five + +Neuroscience 5e Fig. 29.5 + + + +
+ +Note: + + + +--- + +## Functional and anatomical organization of the limbic loop through the basal ganglia + +* Nucleus accumbens– contains MSNs + +* Ventral tegmental area (VTA)– releases dopamine + +Nucleus accumbens + +Neuroscience 5e Fig. 29.10 + + + + + +
+ +Note: + +Much like the direct pathway. Inputs from different parts of cortex, including amygdala. + + + +to MSNs in ventral striatum the nucleus accumbens. These gabaergic projections then inhibit inhibitory projections in the in the ventral globus pallidus called the ventral pallidum. So there is a disinhibitory effect, much as we discussed before for other basal ganglia loops. + + + + + +--- + +--- +