Summary - lectures: amygdala function, dms, hypothalamus + pituitary gland, neurochemical systems PDF

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Amygdala + Hippocampus Amygdala Function: fear and emotion Hippocampus Function: memory formation and recall Sensory stimuli --> Basolateral Nuclei --> Central Nucleus --> expression of fear

Fear Extinction: Prefrontal Cortex has been implicated in extinction of fear by inhibiting the Amygdala's responsiveness  PTSD pts have reduced activity of their prefrontal cortex so amygdala cannot be inhibited well Contextual Fear Conditioning: inputs from Hippocampus (memory) back to the Amygdala connect context with a stressful situation Central nucleus projections to brainstem (raphea, LC, VTA) and hypothalamus (autonomic response) -> expression of fear Amygdala projections to hippocampus and cortex -> experience of fear Amygdala stimulates CRF neurons in HPA Hippocampus inhibits CRF neurons in HPA Anxiety disorders relate to both the hyperactivity of amygdala and the hypoactivity of the hippocampus both leading to hyperactivity of hypothalamic CRF neurons Pathological hyperactivity of basolateral or central nucleus in amygdala or CRF neurons in hypothalamus -> chronic activation of stress response in absence of stressor ->ANXIETY DISORDERS Vicious Cycle: Cortisol stimulates Hippocampus neurons BUT continuous exposure to cortisol can cause degradation of hippocampus neurons

Amygdala + Hippocampus -> Stress response from Amygdala becomes stronger b/c of reduction in hippocampus-mediated feed back inhibition of HPA axis -> leads to greater cortisol release and more hippocampal damage CRF 

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icv administration of CRF produces effects similar to natural stressor effects and are not blocked by removal of pituitary or adrenal gland  Many effects of stress can be attenuated by icv administration of CRF antagonists Amygdala has a lot of CRF neurons and nerve terminals  Stress causes increase of CRF levels in Amygdala  High anxiety = high CRF levels in Amygdala  Intra-amygdaloid CRF causes tachycardia  Intra-amygdalois CRF agonists attenuates shock-induced freezing CRF projections from PVN in hypothalamus to amygdala provides a positive feedback loop

DMS NGF + Alzheimer's Disease Positive Feedback Mechanism 1. Ach released from septal nerve terminals activate hippocampus 2. Causes increase production and release of NGF 3. NGF acts on nerve terminal to promote the survival of cholinergic neurons NGF is a treatment for Alzheimer's as they provide trophic support for neurons in Basal forebrain complex Noradrenergic (NE) Location: LC Activated by: novel, unexpected sensory stimuli Function: increase brain responsiveness Regulates: attention, alertness, vigilance Dopaminergic (DA) Location #1: SNc projects to striatum (caudate and putamen) Function: initiation of voluntary movements  Degradation -> Parkinson's  Antipsychotic drugs are D2 receptor antagonists and create motor disturbances as seen in Parkinson's Location #2: VTA projects to limbic structures (nucleus accumbens and prefrontal cortex) Function: motivated tasks  DA release stimulated by natural rewards and drug rewards  Behaviors seeking these rewards are then reinforced by DA  Antipsychotic drugs target this mesocortical DA system Serotonergic (5-HT) Location: Raphe Nuclei Function: increase brain responsiveness (like NE) Regulates: mood + emotion  Every neuron in CNS is contacted by 5-HT fibers Cholinergic (ACh) Location #1: Basal forebrain complex  First neurons to die in Alzheimer's  Require NGF Function: learning and memory Location #2: Pons and Midbrain tegmentum projects to basal ganglia

DMS and striatum (DA)

Hallucinogens LSD = nonselective 5-HT receptor antagonist due to its similar structure to 5-HT  Agonist at stoma: 5-HT 1A  Agonist at presynaptic terminal: 5-HT 1D  Inhibits synthesis (stoma), firing, and release (presynaptic terminal) of 5-HT  Hallucinations from activation of postsynaptic 5-HT 2A receptors in cerebral cortex Psychostimulants Coke and Amphetamine cause increased alertness, confidence, euphoria, and decrease appetite Sympathomimetic: increase HR + BP, dilate pupils  Enhance DA + NE transmission  Block reuptake transporters to increase synapse [DA] + [NE] 

Addictive because they enhance neurotransmission in the mesolimbic DA system (recall: normal function to reinforce behaviors seeking rewards) and thus reinforce drug-seeking behavior

Hypothalamus + Pituitary Gland Function: autonomic NS, circadian rhythm PVN: hypothalamus has neuroendocrine neurons that extend toward the pituitary gland Receives inputs from the central nuclei of the Amygdala to produce an autonomic response caused by stressors HPA Axis: CRF release is controlled by both the inhibitory inputs from hippocampus (due to cortisol binding) AND excitatory inputs from the amygdala (due to fearful experience) (1) during stress, the PVN secretes CRF into the hypothalamo-pituitary portal circulation (2) CRF triggers release of ACTH from the anterior pituitary gland into general circulation (3) ACTH triggers release of corticosteroids like cortisol from adrenal gland

Amygdala has high concentrations of CRF receptors and terminals CRF projections to amygdala from HPA provide a positive feedback loop Cortisol interacts with glucocorticoid receptors in Hippocampus in inhibit CRF release providing a negative feedback loop/feedback inhibition loop

Hypothalamus + Pituitary Gland

Secretes: Oxytocin + Vasopressin Oxytocin: uterine contractions and ejection of milk from mammary glands Vasopressin: acts on kidneys to retain water and reduce urine production (antidiuretic) Considered to be part of the brain Magnocellular neuroendocrine cells project down stalk into posterior lobe

Secretes: ACTH ACTH: stimulates cortisol release from adrenal glands

Hypothalamus + Pituitary Gland Considered to be a endocrine gland Parvocellular neuroendocrine cells do not extend all the way into the anterior lobe

Neurochemical Systems: Fear & Anxiety Noradrenergic System Location: LC, involved in expression of fear Activity causes symptoms like: insomnia, restlessness, autonomic hyperarousal  

Potentiated release of NE occurs with repeated stress…pts with anxiety disorders are more susceptible to psychosocial stress over time… Repeated stress leads to down-regulation of Alpha2 neurons in the LC (inhibitory autoreceptors) and thus creates hyperactivity of the LC neurons which may underlie the sensitized response to stressors

NE via Beta2 adrenergic receptors + Cortisol via glucocorticoid receptors + CRF via CRF receptors all work together to enhance memory formation in Hippocampus…therefore they are key mediators of consolidated traumatic memories

LC output = NE projections HPA output = CRF projections to amygdala and cortisol

5-HT System and Glucocorticoid Receptor Levels in Hippocampus  Early sensory experience regulates glucocorticoid receptor levels in the hippocampus  A lot of maternal care during the critical period = more glucoritocoid receptors in hippocampus, less CRF in hypothalamus due to more inhibitory feedback = less anxiety as adult and better at handling stress  Maternal influence can be replaced by tactile stimulation which activates the ascending 5HT inputs to hippocampus  5-HT triggers long lasting increase in expression of glucocorticoid receptor gene  Indeed, chronic activation of 5-HT2A receptors causes up-regulation of glucoritocoid receptors Benzodiazepine System  Binding sites present throughout brain, high density in cerebral cortex  Benzos potentiate synaptic action of GABA, both have distinct binding sites  Acute and chronic stress, and panic disorders cause a DECREASE in benzo binding sites

Neurochemical Systems: Fear & Anxiety Opioid System  Acute stress releases endogenous opioids -> hypoalgesia (decrease pain sensitivity)  PTSD shows depletion of endogenous opioids  NE hyperactivity can be reversed by opioids which strongly suppresses LC neurons  PTSD similar to opiate withdrawal which induce hyperactivity of LC neurons (restlessness, etc)

Treatment for Anxiety Disorders  Psychotherapy: designed to reverse effect of fear conditioning to facilitate extinction of fear  Aimed at de-potentiating the potentiated inputs to the amygdala activated by harmless CS Extinction training involves new learning engaging pre-frontal cortex mediated inhibition of the basolateral amygdala

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Anxiolytic: drugs that reduce anxiety, cases resistant to psychotherapy are treated with these  Benzos and SSRIs

Benzos  Highly effective against acute anxiety  Act on GABAa receptors to make GABA more efficient in opening the channel to producing more inhib.  Too much GABA inhibition -> coma

Neurochemical Systems: Fear & Anxiety  Too little -> seizures

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Prolong synaptic actions of 5-HT at receptors by inhibiting reuptake, not immediate like Benzos Anxiolytic effect due to adaptation of brain to chronically elevated brain 5-HT  Adaptive response = increase in glucocorticoid receptors in hippocampus  Chronic activation 5-HT2A receptors causes up-regulation of glucocorticoid receptors in hippocampus Dampen anxiety by enhancing the feedback inhibition of the HPA axis

CRF receptor antagonist Many behavioral effects of natural stress are mediated by release of CRF and subsequent activation of CRF receptors in the brain especially the amygdala  

Injection of CRF in brain can produce full-blown stress responses CRF receptor antagonist will be a new therapeutic drug for the treatment of anxiety disorders...