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@@ -347,3 +347,56 @@ Squire and Kandel. *Memory: From Mind to Molecules* 1999
<div><img src="figs/Neuroscience5e-Fig-08.11-2R_f40021e.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.11, Lee et al., *Nature* 2009</figcaption></div>
---
## 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
<div><img src="figs/ScreenShot2015-05-20at4_501f62c.png" height="400px"><figcaption></figcaption></div>
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
<div><img src="figs/ScreenShot2015-05-20at41_db6891c.png" height="300px"><figcaption></figcaption></div>
Note:
Table 11-2 Selected candidate genes associated with psychiatric disorders.
---
## 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
<div><figcaption class="big">Striatum (caudate, putamen), nucleus accumbens</figcaption><img src="figs/DR2_0af9802.jpg" height="200px"><figcaption>Volkow et al., Synapse 14 (2), 1993, pp. 169-177</figcaption></div>
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---

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## 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.
* 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 (emotional feeling)
* Also tied to somatic muscle responses– especially facial muscles (emotional expression)
* Limbic system– brain areas especially important for emotions (emotional thinking)
* Affective (mood) disorders– e.g. depression
Note:
Abraham Lincoln:
>I am now the most miserable man living. If what I feel were equally distributed to the whole human family, there would not be one cheerful face on earth. Whether I shall ever be better, I cannot tell; I awfully forebode I shall not. To remain as I am is impossible. I must die or be better, it appears to me.
Lincoln was unconscious following a horse kicking him in the head for 24hrs at 9 yrs old.
He was clubbed on the head during a robbery attempt in 1828.
https://en.wikipedia.org/wiki/Medical_and_mental_health_of_Abraham_Lincoln
http://www.theatlantic.com/magazine/archive/2005/10/lincolns-great-depression/304247/
--
## Lincoln's melancholy
Abraham Lincoln:
>I am now the most miserable man living. If what I feel were equally distributed to the whole human family, there would not be one cheerful face on earth. Whether I shall ever be better, I cannot tell; I awfully forebode I shall not. To remain as I am is impossible. I must die or be better, it appears to me.
---
## Visceral (autonomic) motor system
@@ -22,10 +43,10 @@ Note:
Note:
Visceral
: relating to deep inward feelings rather than intellect
---
--
## Autonomic motor system
@@ -40,7 +61,11 @@ 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
Parasympathetic:
Preganglionic is in the brainstem or sacral spinal cord, Peripheral ganglia in close to the organ they control (think ciliary ganglion or cardiac plexus)
sympathetic:
preganglionic is in spinal cord, peripheral ganglia is in the specialized sympathetic chain ganglia
---
@@ -50,22 +75,30 @@ Parasympathetic: Preganglionic is in the brainstem, Peripheral ganglia in DRG
* Duchenne de Boulogne
* Facial muscle stimulation can create a variety of expressions recognizable as emotion
<div><img src="figs/image2_079180b.png" height="200px"><figcaption></figcaption></div>
<div><img src="figs/image2_079180b.png" height="200px"><figcaption>Duchenne de Boulogne *Mecanisme de la Physionomie Humaine* 1862</figcaption></div>
<div><img src="figs/image1_194d0ee.png" height="200px"><figcaption></figcaption></div>
Note:
TODO: img src unknown
Emotions can trigger facial muscles that can’t be done on purpose.
--
## Expression of emotion
<div><img src="figs/Cat-Rage_7be8916.png" height="400px"><figcaption></figcaption></div>
Note:
animals express emotion as well—
---
## Facial expression of emotion
Two pathways to get to facial muscles that display emotion– voluntary and emotional pathways are separable.
<div><img src="figs/Neuroscience5e-Box-29A-2R_d6db3b0.jpg" height="300px"><figcaption>Neuroscience 5e Box 29A</figcaption></div>
<div><img src="figs/Neuroscience5e-Box-29A-2R_d6db3b0.jpg" height="300px"><figcaption>Neuroscience 5e Box 29A, Ross and Mathiesen *N Engl J Med* 1998</figcaption></div>
<div><img src="figs/Neuroscience5e-Box-29A-3R_31abe8e.jpg" height="300px"><figcaption>Neuroscience 5e Box 29A</figcaption></div>
@@ -81,17 +114,6 @@ Extrapyramidal tracts are chiefly found in the reticular formation of the pons a
paresis: muscle weakness
---
## Expression of emotion
<div><img src="figs/Cat-Rage_7be8916.png" height="400px"><figcaption></figcaption></div>
Note:
animals express emotion as well—
---
## Hypothalamus as a coordinator of emotional behavior
@@ -99,10 +121,9 @@ animals express emotion as well—
<div style="font-size:0.7em">
<div></div>
* 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
* 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
@@ -115,10 +136,11 @@ 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)
* 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
<figure><img src="figs/Neuroscience5e-Fig-29.01-0_e39f016.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 29.1</figcaption></figure>
<div style="width:440px"><iframe src="https://www.youtube.com/embed/TtU77nHL-p4" width="420" height="315"></iframe><figcaption>Cat sham rage</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-29.01-0_e39f016.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 29.1, LeDoux *Handbook of Physiology* 1987</figcaption></div>
Note:
@@ -134,11 +156,7 @@ Bard suggested that emotional behaviors are often directed towards self-preserva
## Affective attack expression
* Sham Rage
* An affective attack expression
* Stimulation of medial hypothalamus
<div><img src="figs/Cat-ShamRage_417d68d.png" height="400px"><figcaption></figcaption></div>
<div><figcaption class="big">Sham rage after stimulation of cat medial hypothalamus</figcaption><img src="figs/Cat-ShamRage_417d68d.png" height="400px"><figcaption></figcaption></div>
Note:
@@ -147,7 +165,7 @@ 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
* Both a volitional (with deliberate action) and a non-volitional component. Are in separate pathways. Both pathways ultimately lead to motor neuron 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:
@@ -162,14 +180,16 @@ Note:
Note:
* major targets of the hypothalamus is the reticular formation (tangled nerve web of over 100 cell groups including those that regulate sleep/wakefulness, cardiovascular function, respiration, urination, vomiting, swallowing). Reticular output is to somatic and visceral motor effector systems.
---
## How does your brain impinge on emotions?
## How does your brain regulate 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
* 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:
@@ -186,7 +206,12 @@ 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.
---
orbitofrontal and medial prefrontal cortex together with the amygdala are especially important components of the limbic systm.
* mammilary bodies are part of the posterior hypothalamus and is important for interconnecting the cingulate cortex with the hypothalamus through the anterior nucleus of the thalamus
* hippocampus projects back to the hypothalamus via the fornix
--
## Limbic system
@@ -209,6 +234,30 @@ amgydala—> ventral basal ganglia —> mediodorsal nucleus of thalamus —> orb
amgydala, Latin for ‘almond’
--
## Amygdala
<div><img src="figs/Neuroscience5e-Box-29B-1R_copy_95626bf.jpg" height="400px"><figcaption>Neuroscience 5e Box 29B</figcaption></div>
<!-- <div><img src="figs/Neuroscience5e-Box-29B-2R_copy_f53b71e.jpg" height="100px"><figcaption>Neuroscience 5e Box 29B</figcaption></div> -->
Note:
* amgydala is in the anteior-medial part of the temporal lobe. Rostral to hippocampus
* three major functional and anatomical subdivisions
* medial group
* connections with olfactory bulb and olfactory cortex
* basal-lateral group
* large in humans
* major connections to orbital and medial prefrontal cortex of frontal lobe and association cortex of anterior temporal lobe
* central and anterior group
* connections to hypothalamus and brainstem (visceral sensory structures like nucleus of solitary tract and parabrachial nucleus)
* hypothalamus receives unprocessed sensory inputs, amygdala receives processed sensory inputs (cortex and thalamus)
* highly complex stimuli often needed to evoke response in amygdala (e.g. facelike neurons)
---
## Crude lesion studies
@@ -218,28 +267,30 @@ amgydala, Latin for ‘almond’
* 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)
* Eventually the fear behaviors was narrowed down to a region called the amygdala through selective lesion studies
Note:
* [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)
---
<!--
## Selective lesion studies
* John Downer 1950s UCL
* 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
* Fearsome stimuli in visual hemifield mapping to side of brain with lesioned amygdala showed no fear responses. Fearsome stimuli in visual hemifield mapping to side of brain with intact amygdala then animal shows normal fear behaviors. Therefore the amygdala is required for fear behaviors
Note:
-->
---
## Insights on the role of the amygdala in appraising emotions from patient S.M.
## Patients with amygdala damage exhibit diminished emotional fear recognition and expression
<figure><figcaption class="big">Amygdala damage in patient S.M</figcaption><img src="figs/Neuroscience5e-Box-29D-1R_9161c18.jpg" height="400px"><figcaption>Neuroscience 5e Box 29d</figcaption></figure>
Patient S.M. can’t recognize the emotion of fear in photographs. She also exhibits little fear herself (e.g. to dangerous animals, scary houses, films, etc)
<figure><figcaption class="big">Amygdala damage in patient S.M</figcaption><img src="figs/Neuroscience5e-Box-29D-1R_9161c18.jpg" height="200px"><figcaption>Neuroscience 5e Box 29d</figcaption></figure>
Note:
@@ -249,10 +300,10 @@ She has no motor or sensory or intelligence or memory or language impairment. Ho
---
## Insights on the role of the amygdala in appraising emotions from patient S.M.
## Patients with amygdala damage exhibit diminished emotional fear recognition and expression
<div><img src="figs/image6_9d656c8.jpg" height="400px"><figcaption>Adolphs et al. 1995</figcaption></div>
<div><img src="figs/Picture43_2c79031.png" height="400px"><figcaption>Adolphs et al. 1995</figcaption></div>
<div><img src="figs/image6_9d656c8.jpg" height="400px"><figcaption></figcaption></div>
<div><figcaption class="big">circles: control patients, triangles: amygdala lesion patients</figcaption><img src="figs/Picture43_2c79031.png" height="400px"><figcaption>Adolphs et al., *J. Neurosci* 1995</figcaption></div>
Note:
@@ -260,23 +311,23 @@ Note:
Adolphs et al., 1995. Subject with bilateral amygdala lesions was asked to draw facial expressions of emotions.
<div><img src="figs/image7_ec559be.png" height="400px"><figcaption></figcaption></div>
---
<!--
## 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 that 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:
[#Ramamurthi:1988]: Ramamurthi, B. (1988). Stereotactic operation in behaviour disorders. Amygdalotomy and hypothalamotomy, Acta Neurochir Suppl (Wien), 44(), 152-7. PMID 3066131
-->
---
## 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
* 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 through classical conditioning
* Can use this assay to determine what areas of the brain are required for the learned behavior
Note:
@@ -289,7 +340,7 @@ Note:
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.
<div><img src="figs/ne24_0897_1_4204cd3.jpg" height="300px"><figcaption></figcaption></div>
<div><img src="figs/ne24_0897_1_4204cd3.jpg" height="300px"><figcaption>['Little Albert' experiment](https://en.wikipedia.org/wiki/Little_Albert_experiment), Watson and Rayner *J Exp Psychol* 1920</figcaption></div>
Note:
@@ -301,18 +352,18 @@ As early as the 1920s, fear conditioning was demonstrated in infants. A white r
## Fear conditioning in rats
<figure><img src="figs/50_520a5cf_copy_904c366.jpg" height="400px"><figcaption>Principals of Neural Science, Kandel, Schwarz, Jessel Fig. 50.07</figcaption></figure>
<figure><figcaption class="big">Conditioned fear response in rats after associating foot shocks with sound</figcaption><img src="figs/50_520a5cf_copy_904c366.jpg" height="400px"><figcaption>Principals of Neural Science, Kandel, Schwarz, Jessel Fig. 50.07</figcaption></figure>
Note:
notice incr blood pressure, visceral response after the association is made and how it is maintained
---
## Pathways involved in fear conditioning
<figure><img src="figs/Neuroscience5e-Fig-29.05-0_63e692d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.5</figcaption></figure>
<figure><figcaption class="big">Amygdala can associate diverse sensory inputs</figcaption><img src="figs/Neuroscience5e-Fig-29.05-0_63e692d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.5</figcaption></figure>
Note:
@@ -324,104 +375,93 @@ Note:
-->
---
<!--
## Amygdala: fear conditioning
Sensory input
Motor output
Sensory input
<div><img src="figs/image8_965cc20.png" height="300px"><figcaption></figcaption></div>
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.
--
## Important properties of LTP
---
## Long term potentiation (LTP)
* Spatial localization (synaptic input specificity)
* Associativity (between synapses within the post-synaptic neuron)
<figure><img src="figs/Neuroscience5e-Fig-08.09-0r_17f2f6b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.9</figcaption></figure>
Note:
TODO: review this figure legend
* Properties consistent with role as specific coincidence detector
* Not generalized across whole neuronal ensembles, but localized
* Associativity utilized for associative learning or classical/Pavlovian conditioning (great early 20c russian physiologist, Pavlov's dogs (dinner bell association with food presentation and salivation))
NMDA receptor opening leads to strengthening of synapses
**LTP in the amygdala**
---
## Insertion of more AMPA receptors in synapse
<figure><img src="figs/Neuroscience5e-Fig-08.13-0_b08c55e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.13</figcaption></figure>
Note:
---
## Spine growth, more synapses between neurons
<figure><img src="figs/Neuroscience5e-Fig-08.15-1R_c375165.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.15</figcaption></figure>
Note:
at Schaffer collateral axon synapse betwen CA3 and CA1
* NMDA receptor opening leads to strengthening of synapses
* weak stimulation at pathway 2 can lead to synapse strengthening/potentiation through associative mechanisms-- EPSP summation
---
## Model for associative learning in the amygdala
<div><img src="figs/Neuroscience5e-Fig-29.06-0_5f1d954.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.6</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-29.06-0_5f1d954.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.6, E.T. Rolls *The Brain and Emotion* 1999</figcaption></div>
Note:
---
## The amygdala as a key node in the brain network for emotional processing
<figure><img src="figs/Neuroscience5e-Box-29B-3R_copy_cb4899d.jpg" height="400px"><figcaption>Neuroscience 5e Box 29B</figcaption></figure>
Note:
orbito and medial prefrontal cortex
: prefrontal cortical regions in the frontal lobe associate information from every sensory modality
- amygdala projects to mediodorsal nucleus of thalamus-- this in turn projects to the prefrontal association areas
- innervates nueons in ventral basal ganglia that receive major corticostriatal projections
Amgydala and connections to prefrontal cortex and basal ganglia regulates selction and initiation of behaviors need to obtain rewards (and avoid punishments)
Feelings may be a kind of emotional working memory. Containing both immediate conscious experience of implicit emotions and explicit processing of semantic thought, orbito and medial sectors likely areas for these assocaition be maintained in conscious awareness
---
## Model for the awareness of emotional feelings
<figure><img src="figs/Neuroscience5e-Fig-29.07-0_8dff24b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.7</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-29.07-0_8dff24b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.7, LeDoux 2000</figcaption></figure>
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.
* 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:
smile asymmetries in facial expressions, most individuals more quickly and fully express emotions with left facial musculature than the right
---
@@ -435,14 +475,12 @@ Note:
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)
* Monoamine oxidase inhibitors that increase monoamine concentration at synaptic terminals– e.g. Iproniazid
* Monoamine transporter inhibitors– e.g. Imiprmine and fluoxetine (Prozac). Fluoxetine selectively inhibits serotonin reuptake as a selective serotonin reuptake inhibitor
Note:
@@ -452,7 +490,7 @@ 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
* 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
@@ -460,15 +498,14 @@ Note:
Note:
---
--
## Benzodiazepine mechanism of action
* Benzodiazepines increase the affinity of the receptor for GABA
* Barbituates can activate the GABA receptor independent of GABA
<div><img src="figs/ScreenShot2015-05-20at111_cfb3f12.png" height="400px"><figcaption></figcaption></div>
<div><img src="figs/ScreenShot2015-05-20at111_cfb3f12.png" height="300px"><figcaption></figcaption></div>
Note:
@@ -481,28 +518,32 @@ Act at the level at the interface of the alpha and gamma subunits. Different ne
## 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
* Most known drugs of abuse (heroin, cocaine, ethanol, opiates, marijuana, nicotine, amphetamines) act on the limbic circuits
* Most act by altering dopamine circuits that go through the ventral basal ganglia
Note:
all act by changing the neuromodulatory influence of dopamine for processing reinforement signals in nucleus accumbens, leading to the strenghthening of circuits underlying addictive behavior in limbic systems
---
## Functional and anatomical organization of the limbic loop through the basal ganglia
* Nucleus accumbens– contains MSNs
* Ventral tegmental area (VTA)– releases dopamine
* Ventral tegmental area (VTA)– provides dopaminergic input to the to nucleus accumbens
<figure><img src="figs/Neuroscience5e-Fig-29.10-0_b9e426d.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 29.10</figcaption></figure>
Note:
Recall the non-motor loops we discussed in our study of the basal ganglia.
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.
nucleus accumbens and VTA are the main sites wher drugs of abuse interact with signals for emotional reward
serotonin pathways
* mood
@@ -522,14 +563,22 @@ dopamine pathways
## Changes in the activity of dopamine neurons in the VTA during stimulus–reward learning
<figure><img src="figs/Neuroscience5e-Fig-29.12-0_copy_1aa680f.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.12</figcaption></figure>
Recordings from VTA dopamine neurons in awake monkey. VTA signals the presence of an **expected** reward
<figure><figcaption class="big">
Raster plots of experiment trial showing spike times and peristimulus time histograms.
top: Surprise juice reward response
middle: Learned conditioned stimulus (e.g. visual cue) and presence of expected reward
bottom: Learned conditioned stimulus and absence of expected reward
</figcaption><img src="figs/Neuroscience5e-Fig-29.12-0_copy_1aa680f.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 29.12, Schultz 1997</figcaption></figure>
Note:
The VTA signals the occurrence of a reward relative to its prediction
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- Schultz Neuron 1997
--
## Stimulation of reward pathway is incredibly powerful
@@ -546,47 +595,19 @@ The VTA signals the occurrence of a reward relative to its prediction
Note:
---
## Key components of reward circuits
## Drugs of abuse affect dopamine projections from the VTA to the nucleus accumbens
<div style="font-size:0.7em">
<div></div>
<div><figcaption class="big">Synaptic locations of action for psychoactive drugs of abuse</figcaption><img src="figs/Neuroscience5e-Fig-29.11-1R_copy_9e75248.jpg" width="500px"><figcaption>Neuroscience 5e Fig. 29.11</figcaption></div>
<div><figcaption class="big">Functional changes at VTA projections in addicted individuals</figcaption><img src="figs/Neuroscience5e-Fig-29.11-2R_copy_d09517f.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 29.11</figcaption></div>
1. Mesolimbic (dopamine pathway):
- Neurons from ventral tegmental area (VTA) to nucleus accumbens (major neurotransmitter is dopamine)
- Critical pathway for drug addiction
5. VTA– nucleus accumbens pathway
- Acts as a rheostat of reward. Tells 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
2. Amygdala:
- Helps 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:
- Coordinates and processes all this information and determines ultimate behavior of the individual
</div>
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.
---
## 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
@@ -603,7 +624,14 @@ Specifically, studies in primates and rodents have shown that many VTA dopamine
<!-- <div><img src="figs/ScreenShot2015-05-18at4_871d504.png" height="400px"><figcaption></figcaption></div> -->
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long-term changes addicts:
* Decreases in CREB transcription factor in NAc (and extended amygdala)
* Decreases in metabolism in orbito frontal cortex (OFC)
* Decreases in dopamine D2 receptor binding
--
## Drugs of abuse act on endogenous neurotransmitter receptors and transporters
@@ -644,68 +672,47 @@ VMAT2: vesicular monoamine transporter, intracellular
-MDMA enters monoamine neurons by acting as a monoamine transporter substrate (i.e., a substrate for DAT, NET, and SERT)
---
## Drugs of abuse affect dopamine projections from the VTA to the nucleus accumbens
<div><figcaption class="big">Synaptic locations of action for psychoactive drugs of abuse</figcaption><img src="figs/Neuroscience5e-Fig-29.11-1R_copy_9e75248.jpg" width="500px"><figcaption>Neuroscience 5e Fig. 29.11</figcaption></div>
<div><figcaption class="big">Functional changes at VTA projections in addicted individuals</figcaption><img src="figs/Neuroscience5e-Fig-29.11-2R_copy_d09517f.jpg" width="400px"><figcaption>Neuroscience 5e Fig. 29.11</figcaption></div>
## 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:
Exposure to drugs of abuse causes long-lasting enhancement of excitatory input to VTA dopamine neurons, increasing AMPA/NMDA receptor ratio at these synapses.
23 percent of individuals who use heroin become dependent on it. Altered conscious regulation of your behavior. 1 in 5.
http://stopthedrugwar.org/chronicle/2008/apr/18/addiction_small_percentage_drug
>hallucinogens and sedatives, the figure was 2%; for pain relievers and alcohol, 3%. The drug with the highest number of dependent users a year after first use was heroin (13%), followed by crack cocaine (9%), marijuana (6%), stimulants (5%), and powder cocaine (4%)
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## Long-term changes in the brain as a result of abuse
## Key components of limbic system reward circuits
* Decreases in CREB transcription factor in NAc (and extended amygdala)
* Decreases in metabolism in orbito frontal cortex (OFC)
* Decreases in dopamine D2 receptor binding
<div style="font-size:0.7em">
<div></div>
<div><figcaption class="big">Striatum (caudate, putamen), nucleus accumbens</figcaption><img src="figs/DR2_0af9802.jpg" height="200px"><figcaption>Volkow et al., Synapse 14 (2), 1993, pp. 169-177</figcaption></div>
1. Mesolimbic (dopamine pathway):
- Neurons from ventral tegmental area (VTA) to nucleus accumbens (major neurotransmitter is dopamine)
- Critical pathway for drug addiction
5. VTA–nucleus accumbens pathway:
- Acts as a rheostat of reward. Tells 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
2. Amygdala:
- Helps 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 cortical regions:
- Coordinates and processes all this information and determines ultimate behavior of the individual
</div>
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
<div><img src="figs/ScreenShot2015-05-20at4_501f62c.png" height="400px"><figcaption></figcaption></div>
Note:
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## 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
<div><img src="figs/ScreenShot2015-05-20at41_db6891c.png" height="300px"><figcaption></figcaption></div>
Note:
Table 11-2 Selected candidate genes associated with psychiatric disorders.
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