2017 renames

limbic.md

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+## Emotions
+
+* 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
+
+* 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
+
+
+<figure><img src="figs/Neuroscience5e-Fig-21.01-0_a5e4149.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 21.1</figcaption></figure>
+
+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 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  
+
+
+---
+
+## Facial expression of emotion
+
+* 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>Duchenne de Boulogne *Mecanisme de la Physionomie Humaine* 1862</figcaption></div>
+<div><img src="figs/image1_194d0ee.png" height="200px"><figcaption></figcaption></div>
+
+Note:
+
+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, 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>
+
+
+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
+
+---
+
+## Hypothalamus as a coordinator of emotional behavior
+
+<div style="font-size:0.7em">
+<div></div>
+
+* Hypothalamus as a critical center for coordination of both the autonomic and somatic components of emotional behavior
+* Lesion huge areas of the forebrain in cats and angry behavior occurs spontaneously, including the 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
+
+</div>
+
+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
+
+<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:
+
+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).
+
+---
+
+## Affective attack expression
+
+<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:
+
+
+---
+
+## 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 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:
+
+
+---
+
+## Descending systems that control somatic and visceral motor pathways in the expression of emotion
+
+<figure><img src="figs/Neuroscience5e-Fig-29.02-0_adc3a03.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.2</figcaption></figure>
+
+
+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 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**
+
+Note:
+
+
+---
+
+## Limbic system
+
+<figure><img src="figs/Neuroscience5e-Fig-29.04-1R_d02b409.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.4</figcaption></figure>
+
+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.
+
+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
+
+<div><figcaption class="big">Limbic system</figcaption><img src="figs/image3_c086c29.png" height="400px"><figcaption></figcaption></div>
+<div><figcaption class="big">Basal ganglia</figcaption><img src="figs/image4_0a779a9.png" height="400px"><figcaption></figcaption></div>
+
+Note:
+
+TODO: img src unknown
+
+---
+
+## Limbic system
+
+<figure><img src="figs/Neuroscience5e-Fig-29.04-2R_c8005b8.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 29.4</figcaption></figure>
+
+Note:
+
+amgydala—> ventral basal ganglia —> mediodorsal nucleus of thalamus —> orbital and medial prefrontal cortex —> amygdala
+
+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
+
+* 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 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
+* 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
+
+ -->
+
+---
+
+## Patients with amygdala damage exhibit diminished emotional fear recognition and expression
+
+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:
+
+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). 
+
+---
+
+## Patients with amygdala damage exhibit diminished emotional fear recognition and expression
+
+<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:
+
+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
+
+
+[#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 through classical conditioning
+* 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.
+
+<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:
+
+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
+
+<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><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:
+
+<!-- 
+## Physiological pathways for amygdala mediated fear conditioning
+
+<div><img src="figs/image11_d57630d.png" height="400px"><figcaption></figcaption></div>
+
+ -->
+
+<!-- 
+## Amygdala: fear conditioning
+
+Sensory input
+Motor output
+Sensory input
+
+<div><img src="figs/image8_965cc20.png" height="300px"><figcaption></figcaption></div>
+
+-->
+
+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
+
+* 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:
+
+* 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))
+
+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, 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, 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
+
+Note:
+
+smile asymmetries in facial expressions, most individuals more quickly and fully express emotions with left facial musculature than the right
+
+---
+
+## 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
+
+* 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:
+
+
+---
+
+## 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
+
+<div><img src="figs/ScreenShot2015-05-20at111_cfb3f12.png" height="300px"><figcaption></figcaption></div>
+
+Note:
+
+TODO: img src unknown
+
+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 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)– 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
+* memory processing
+* sleep
+* cognition
+
+dopamine pathways
+* reward (motivation)
+* pleasure, euphoria
+* motor function (fine tuning)
+* compulsion
+* perserverance
+* decision making
+
+---
+
+## Changes in the activity of dopamine neurons in the VTA during stimulus–reward learning
+
+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
+
+- Schultz Neuron 1997
+
+--
+
+## Stimulation of reward pathway is incredibly powerful
+
+<div style="font-size:0.8em">
+<div></div>
+
+* Self stimulation experiments have demonstrated that rats will bar press for stimulation of the VTA or NAc
+* Olds and Milner, 1954, J Comp Physiol Psychol, 47
+* This behavior can be blocked by cutting the pathway from the VTA or by administering dopamine antagonists
+
+</div>
+
+<div><iframe src="https://www.youtube.com/embed/aNXhyPj-RsM" width="420" height="315"></iframe><figcaption>Rat self reward stimulation</figcaption></div>
+
+Note:
+
+---
+
+## 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>
+
+
+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.
+
+--
+
+## 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 
+
+<!-- <div><img src="figs/ScreenShot2015-05-18at4_871d504.png" height="400px"><figcaption></figcaption></div> -->
+
+
+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
+
+<div style="font-size:0.7em">
+<div></div>
+
+Drug           | Endogenous ligands           | Mechanism of action                                          
+-------------- | ---------------------------- | -------------------------------------------------  
+Nicotine       | acetylcholine                | Agonist of ligand gated channels (nAChR)                              
+THC            | anandamide, 2AG              | Agonist of cannabinoid receptors (GPCRs)                      
+Opioids        | enkephalin, ß-endorphin, Dynorphin | Agonist of opioid GPCRs (µ,∂,k)                            
+Cocaine        |                              | Inhibits 5-HT transporters, DAT, NET. Increased DA, NA, 5-HT in synaptic cleft.
+Amphetamine    |                              | Inhibits MAO, NET, and VMAT. Increased DA and NA in synaptic cleft.
+MDMA (ecstasy) |                              | Inhibits 5-HT transporters and VMAT. Increased DA, 5-HT, NA in synaptic cleft.
+
+</div>
+
+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)
+
+
+---
+
+## 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:
+
+23 percent of individuals who use heroin become dependent on it. Altered conscious regulation of your behavior.  1 in 5. 
+
+
+
+http://www.samhsa.gov/  
+number of dependent users a year after first use 2008:  
+
+- hallucinogens and sedatives 2% 
+- pain relievers and alcohol 3% 
+- heroin 13%
+- crack cocaine 9% 
+- marijuana 6% 
+- stimulants 5%
+- powder cocaine 4%
+
+
+---
+
+## Key components of limbic system reward circuits
+
+<div style="font-size:0.7em">
+<div></div>
+
+1. VTA–nucleus accumbens pathway:
+    - Dopamine 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
+    - Neurons from ventral tegmental area (VTA) to nucleus accumbens (major neurotransmitter is dopamine)
+    - Critical pathway for drug addiction
+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:
+
+---
+
+## Exam bonus points!
+
+5 bonus points on the final exam for every person if <span style="color:red">**≥51%** of the class submits teaching evaluations</span> (for myself and TAs) by <del>Thursday Dec 8</del> <ins> **Sun Dec 4**</ins> (apparently there is some sort of evaluation window/deadline that ends earlier than expected, sorry for the confusion!)
+