Chemical Control of the Brain and Behavior

The Chemical Control of the Brain and Behavior

  • High precision signaling vs. diffuse signals:
    • Specific synapses, tightly regulated, and restricted to seconds in time.
    • More diffuse signals over longer durations conveying information about overall state.
  • Three main systems:
    • Secretory hypothalamus & stress.
    • The autonomic nervous system.
    • Diffuse neuromodulatory systems of the brain.

The Secretory Hypothalamus

  • Part of the diencephalon below the thalamus with many nuclei.
  • Regulates homeostasis like a thermostat, maintaining a narrow, optimal physiological range.
    • Temperature, blood pressure, salinity, glucose and stress responses, social behavior, feeding, sleep, and more.
  • Zones and Nuclei:
    • Lateral, Medial, & Periventricular zones.
    • Periventricular zone releases factors to the blood stream.
    • Composed of interconnected nuclei with different functions.
    • Connected to the pituitary gland

The Pituitary Gland

  • Extends below the brain in a bone cradle.
  • Anterior & Posterior Lobes form a “mouthpiece” by which the brain speaks to the body.
  • Two modes of communication.

The Posterior Pituitary

  • Magnocellular neurosecretory cells in the hypothalamus project here.
  • Releases Oxytocin and Vasopressin into the blood stream.
    • Oxytocin: important for social behavior, parturition, and lactation.
    • Vasopressin: anti-diuretic hormone (ADH), regulates water balance and social behavior.

The Anterior Pituitary

  • Parvocellular neurosecretory cells in the hypothalamus project here.
  • The anterior pituitary is an actual gland that secretes hormones in response to hypothalamic inputs.
  • Hypophysiotropic hormones from hypothalamus are released into the hypothalamic-pituitary portal circulation and stimulate or inhibit AP hormone secreting cells.

Hormones Made by the AP

  • Follicle-stimulating hormone (FSH).
    • Target: Gonads.
    • Action: Ovulation, spermatogenesis.
  • Luteinizing hormone (LH).
    • Target: Gonads.
    • Action: Ovarian and sperm maturation.
  • Thyroid-stimulating hormone (TSH).
    • Target: Thyroid.
    • Action: Thyroxin secretion (increases metabolic rate).
  • Adrenocorticotropic hormone (ACTH).
    • Target: Adrenal cortex.
    • Action: Cortisol secretion (mobilizes energy stores, inhibits immune system, other actions).
  • Growth hormone (GH).
    • Target: All cells.
    • Action: Stimulation of protein synthesis.
  • Prolactin.
    • Target: Mammary glands.
    • Action: Growth and milk secretion.
  • Hypothalamic-Pituitary-Adrenal (HPA axis) controls stress responses (cortisol release).

Feedback Loops

  • Thermostat-like function allows for maintenance of homeostasis.
  • Neurosecretory cells of the hypothalamus are sensitive to the hormones secreted in their pathways – so when levels get too high they can shut off more production.

What is Stress?

  • Stressors come in many flavors - acute vs. chronic, physical vs. psychological etc.

  • Acute physical stressors

    • Physical exertion
    • Acute injury
    • Predator-prey interaction

  • Chronic physical stressors

    • Illness
    • Starvation
    • Obesity
    • Altitude exposure
    • Heat/cold exposure

The Stress Response: Fight or Flight!

  • Attention & vigilance
  • Saliva production
  • Digestion
  • Filtration
  • Food Movement
  • Reproduction
  • Pupil dilation
  • Breathing
  • Blood pressure and heart rate
  • Blood sugar and fat concentrations
  • Vessel constriction
  • Contraction strength (trembling)

The HPA Axis

  1. Stressor is perceived.
  2. The hypothalamus releases corticotropic releasing hormone (CRH) into the hypophyseal portal system.
  3. Anterior pituitary cells secrete ACTH in the bloodstream in response to CRH.
  4. The adrenal cortex releases glucocorticoid hormones (GCs) in the systemic blood circulation.
  5. Systemic GCs stimulate metabolism and suppress immune function.
  6. GCs circulate back into the brain and stimulate GC receptors, providing negative feedback at multiple levels.

Interrupted feedback loop

  • Prednisone – synthetic steroid/form of cortisol – anti-inflammatory – The body thinks that cortisol levels are very high, so it shuts off secretion!
  • If prednisone is stopped to quickly the body can’t turn on cortisol again fast enough – Adrenal insufficiency = low blood pressure, abdominal pain, mood/emotional changes
  • Addison’s Disease = degeneration of the adrenal gland – leads to fatigue, skin discoloration, stomach pain, weight loss, mood changes
  • Cushing’s Disease = the opposite! Anterior pituitary releases too much ACTH – rapid weight gain, sleeplessness, memory impairment, immunosuppression, irritability

Adaptive Stress

  • Eustress: optimal level of stress that promotes focused attention, emotional regulation, and rational thinking.
  • Distress: Too much stress results in impaired memory, burnout, and impaired executive functions.

Modern life presents many chronic stressors that are psychological rather than physical

  • Personal conflict
  • Acute frustration
  • Financial
  • Grief and Loss
  • School and career
  • Care-giving

Chronic Stress

  • Chronic Stress can cause the negative feedback loop to breakdown –
    • Chronically high levels of cortisol can cause atrophy of the dendrites in places like the hippocampus that express glucocorticoid receptors, less responsive to feedback.
  • In primates and other animals with social hierarchy, low-ranking individuals experience chronically high levels of stress leading to ulcers, colitis, memory impairments, immunosuppression, atherosclerosis and more.

Stress Perception

  • What is very stressful to one person could be fun to someone else – e.g. public speaking
  • Lots of factors moderate how stressors impact physiology long term
    • When they occur in the lifespan
    • How severe they are
    • Whether you have social support
    • Genetics
    • How much control you have over the situation
  • Susceptibility vs. Resilience to stress is a balance of all these factors

Stress Controllability

  • Control over a stressor can lessen the negative consequences of that stress exposure.
  • Control over stress activates the PFC and blocks some of the negative outcomes
  • Uncontrollable stress can lead to a “learned helplessness” phenotype

The Autonomic Nervous System

  • Periventricular hypothalamus also controls the Autonomic Nervous System (ANS).
  • Autonomic = automatically carried out without conscious control.
  • Two divisions:
    • The Sympathetic: increases heart rate and blood pressure, mobilizes glucose reserves, suppresses digestion, etc. “Fight or flight”
    • The Parasympathetic: decreases heart rate and blood pressure, promotes digestion, etc. “rest and digest”

Stress Increases Sympathetic Nervous System

  • Relaxes airways.
  • Dilates pupils and inhibits salivation.
  • Increases heart rate.
  • Stimulates glucose production and release.
  • Stimulates the release of adrenaline.
  • Inhibits digestion.
  • Inhibits voiding of bladder.
  • Stimulates orgasm.

Stress Decreases Parasympathetic Nervous System

  • Constricts pupils and stimulates tear production and salivation.
  • Constricts airways.
  • Slows heart rate.
  • Stimulates digestion.
  • Stimulates voiding of bladder.
  • Stimulates erection of genitals.

Somatic Motor System vs. ANS

  • Somatic Motor system: Controls skeletal muscle, cell bodies in the brainstem or ventral spinal cord.
  • ANS: Cell bodies OUTSIDE the CNS In autonomic ganglion Before these ganglion = preganglionic fibers After ganglion = Postganglionic fibers Release Acetylcholine and Norepinephrine.
  • Sympathetic preganglionic fibers emerge from middle (Thoracic and Lumbar spinal cord), while parasympathetic = Brainstem and Sacral.
  • Parasympathetic = post ganglionic cells are very close to, or on, target organs.
  • Sympathetic axons release norepinephrine onto target tissues, Parasympathetic release Acetylcholine.

Diffuse Neuromodulatory Systems

  • Share many common features:
    • Small sets of neurons, typically in the brainstem
    • Give rise to widespread projections throughout the cortex – 1 neuron can contact 100,000 postsynaptic cells!!
    • Release neurotransmitters that can diffuse through extracellular space as well as in the synaptic cleft
    • Use lots of gPCR mechanisms
    • Allows them to regulate brain states – like arousal/sleep vs. waking, motivation, mood, attention, etc.

Chapter 16: Motivation

  • Definition: Driving force on behavior.
  • Motivation drives Behavior.
  • Homeostasis drives Motivation.
  • The Hypothalamus drives Homeostasis.

Ways to Maintain Homeostasis

  • Motivation drives voluntary mechanisms to return to homeostasis.
  • Examples: Hunger, thirst, cold.

Hunger: The Motivation to Eat

  • Body weight is normally very stable.
  • Weight lost during a period of starvation is rapidly gained when food is freely available.
  • Similarly, if an animal is force fed, it will gain weight, but the weight is lost as soon as the animal can regulate its own food intake.

Energy Balance in the Body: Two States

  • The Prandial State: Right after we eat a meal, and the blood is filled with nutrients
    • Energy is stored in 2 forms: glycogen and triglycerides
      • Glycogen = short term and finite – liver and skeletal muscle
      • Triglycerides = long term in adipose (fat) tissue – virtually unlimited
    • Anabolism = the assembly of these macromolecules (glycogen + triglycerides) from simple precursors
  • The Postabsorptive State: When these macromolecules are broken down to provide the body with energy for cellular metabolism
    • Catabolism = the breakdown of these macromolecules for use

Energy Balance

  • Requires mechanisms to regulate feeding behavior depending on:
    • The size of energy reserves
    • Their rate of replenishment
  • The Lipostatic Hypothesis: Gordon Kennedy (1953) – that the brain monitors the amount of body fat and works to protect this energy store
Long Term Regulation of Feeding Behavior: How Does Adipose Tissue Communication With the Brain?
  • Mice lacking the ob gene: ob/ob mice.
  • This gene codes for something that tells the brain that fat reserves are normal/adequate.
  • 1994: Leptin.

Leptin

  • Leptin is released from adipocytes and regulates feeding by acting on the neurons in the hypothalamus to decrease feeding and increase energy expenditure.
  • BUT, leptin wasn’t the wonder drug it was hoped, not very effective in typical people (only leptin-deficient individuals)

Feeding and the Hypothalamus

  • Lesions of Lateral Hypothalamus = anorexia
  • Lesions of ventromedial hypothalamus = overeating
  • Early lesions studies: hunger and satiety ‘centers’ in the hypothalamus
  • More recent studies: centers is too simplistic- more about the precise where and when and what of hormone signaling

When Leptin Levels are High

  • High circulating leptin activates leptin receptors on neurons in the arcuate nucleus.
    • These neurons make ⍺MSH/CART.
    • These neurons project to paraventricular nucleus → stimulate ACTH and Thyrotropin release from the AP – to raise metabolism
    • Activate Sympathetic ANS to increase metabolic rate
    • Project to the Lateral Hypothalamic Area to INHIBIT feeding

When Leptin Levels are Low

  • Low/falling circulating leptin activates leptin receptors on neurons in the arcuate nucleus.
    • These neurons make NPY/AgRP.
    • Inhibit ACTH and Thyrotropin release from the AP – to decrease metabolism
    • Activate Parasympathetic ANS to decrease metabolic rate
    • Project to the Lateral Hypothalamic Area to STIMULATE feeding
  • NPY/AgRP = OREXIGENIC peptides -‘appetite’

Control of Feeding by Peptides in the Lateral Hypothalamus

  • Other peptides in the LH are sensitive to inputs and regulate feeding behavior:
    • MCH neurons in the LH: melanin-concentrating hormone –
    • Orexin neurons in the LH: also called hypocretin – wakefulness
  • Both have widespread connections throughout the cortex and limbic system and can therefore mediate movement and action towards feeding
  • Rise in the brain as leptin levels fall
  • Orexin may promote meal initiation, while MCH prolongs food consumption

Short Term Regulation of Feeding Behavior: Feeling Full and Hungry

  • Orexigenic and satiety signals regulate feeding behavior.
  • Satiety signals rise in response to feeding.
  • When satiety signals are high, food consumption is inhibited.
  • When the satiety signals fall to zero, the inhibition is eliminated, and food consumption ensues
Some Important Mediators
  • Ghrelin: the main hunger signal – released by the stomach into the bloodstream when the stomach is empty – growling - activates NPY/AgRP neurons in the Arcuate Nucleus
  • Gastric distension– a fullness signal– mechanoreceptors sends signals to the nucleus of the solitary tract (ANS control) via the vagus nerve
  • Cholecystokinin– a fullness signal– released by the intestine when fatty foods are consumed via the vagus nerve
  • Insulin– a critical regulator of blood sugar – can also act directly on the hypothalamus to regulate feeding….

Insulin, Blood Glucose, and Feeding Behavior

  • Insulin = released by β cells in the pancreas
    • required for the transport of glucose from the blood to other cells of the body
  • blood glucose is tightly regulated by insulin: low insulin = high blood glucose high insulin = low blood glucose
  • Insulin is highest after we have eaten and glucose reaches our blood stream
  • Also serves as a satiety signal by directly Interacting with Arcuate neurons

Diabetes and Insulin

  • Type 1 Diabetes = genetic autoimmune disease where the immune system kills β cells in the pancreas - leads to high blood glucose/inability to use glucose - treated with insulin injections
  • BUT too much insulin/overdose can cause blood sugar to plummet – causing insulin shock – delirium, dizziness, tremors, loss of consciousness. Why? Brain uses so much sugar!!
  • Type 2 Diabetes = acquired insulin resistance – cells stop responding efficiently to insulin, also leading to high blood sugar

Why Do We Eat?

  • Wanting vs. liking
    • We eat because it tastes good! It is a pleasurable, hedonic experience
    • We also eat because we are hungry – drive reduction – it satisfies a craving
  • Animal and human research suggests these are separate circuits in the brain
  • WANTING
  • LIKING
Reinforcement and Reward
  • Olds & Milner, 1950, McGill University
  • Implanted stimulating electrodes into the brains of rats, provided a lever that rats could press to receive stimulation
  • Only in some brain regions – rats would press for stimulation : electrical self-stimulation
  • Provided a reward (stimulation) that reinforced the behavior (lever pressing)
  • Stimulation of dopamine system – particularly arising from the Ventral Tegmental Area was most rewarding

Dopamine

  • Mesocorticolimbic Dopamine System
  • This pathway seems to be incredibly important for motivation for food reward – the seeking, craving, etc. i.e. working hard to get something to satisfy a drive or craving “wanting”
  • Critical for all kinds of natural rewards, but also drugs (cocaine, amphetamine, heroin, etc.)
  • Pleasure/liking is dissociable – other neurotransmitter systems like opioids and endocannabinoids.

Chapter 18: Emotion

  • Affective Neuroscience: The investigation of the neural basis of emotion and mood
  • Emotional expression: Facial or bodily responses/behavior that we associate with a particular feeling ≠ Emotional experience: Feelings themselves
  • Emotions = Feelings

Theories of Emotion

  • Paul Ekman, 1970s: Six basic, universal emotions: Anger, Sadness, Fear, Disgust, Surprise, Happiness
  • Studied these across cultures (U.S., Japan, Argentina, Chile, Papua New Guinea) to show that these are cross-cultural, not dependent on language, etc. (but…)
  • Neural activation patterns differ for different emotions
  • Participants across the world report different emotions as having different representations within the body.
  • Lisa Feldman-Barrett argues that 6 basic, universal emotions is inaccurate.
    • Reflects Western ideas.
    • Not necessarily true across all cultures or even all individuals/within a given individual.
    • CONTEXT is actually hugely important for both understanding and feeling emotions.
Neural Circuits for Emotion
  • More subjective – harder to know what someone is feeling based on physical expressions
  • Animals can’t tell us what they are feeling
  • There is still quite a bit we don’t know about how emotion is coded in the brain
    • Lots of theories have been proposed
    • Our view of how emotion is encoded in the brain has evolved
    • Most up-to-date: Emotions are based in distributed networks/circuits of brain activity

Early Theories of Emotion

  • The James-Lange Theory of Emotion

    • William James (1884) & Carl Lange
    • We experience emotion in response to physiological changes in our body

  • The Cannon-Bard Theory of Emotion

    • Walter Cannon & Phillip Bard (1927)
    • We can experience emotion without signals from the body
      • Individuals with damage to the spinal cord can still feel emotions
      • Physiological states don’t map 1:1 with emotions

  • Stimuli can influence our emotions even without conscious perception Conditioning phase: fMRI: amygdala activity Testing phase:

Origins of Emotion

  • Broca – 1878: The ‘Limbic Lobe’ – ‘Limbus’ in latin. Sits around the border of the brain stem
  • James Papez – 1930s: The Papez Circuit – thought that these regions regulated emotion along with the hypothalamus
  • Lesions and/or tumors in the cingulate cortex alter emotional expression without changing perception or intelligence
Problems with the Idea
  • Many of the regions in the Papez circuit have proven to be important, but others have not (or at least not strongly)
    • Anterior cingulate & hypothalamus: yes
    • Anterior thalamus & hippocampus: not so clearly
  • Given multiple emotions, no reason to think that all emotions are necessarily governed by the same circuit
  • Most of these regions do other things as well
Anterior Lobe
  • Phineas Gage; (1848) Had a tamping rod go through his eye socket and out the top of his head, but healed. However, he was “no longer Gage” His personality was entirely changed.
  • Anterior Cingulate Cortex: understanding and cognitively appraising interoceptive information & assigning conceptual meaning to sensations
  • The orbitofrontal cortex and emotion: Important for using memories and imagined futures to determine emotional responses, helps to assign valence (good or bad, etc.) to stimuli in the environment.
  • The Insular cortex (insula) and emotion: Receives lots of interoceptive information (from inside the body), primary gustatory cortex Stimulation of insula leads to sensations of disgust Additionally involved in social emotions like empathy, trust, intuition and more…
Fear and the Amygdala
  • Fear is relatively easier to study in rodent models than some other emotions
  • Work in both animal models and human studies suggest that the amygdala is important for fear
  • Importantly, however, the amygdala regulates other behaviors/emotions as well
  • And other brain regions also regulate fear – Fear is activity within a large neural network of which the amygdala is an important part
  • The amygdala sits in the medial temporal lobe and is comprised of several subdivisions/nuclei: Medial amygdala, Central amygdala, Basolateral amygdala, Cortical amygdala
Related Research
  • Animals with lesions/removal of the temporal lobes demonstrated very strange behavior – termed Kluver-Bucy Syndrome
    • Altered visual perception
    • Oral fixation
    • Hypersexuality
    • Absence of fear responses
  • Patient S.M. had a rare case of bilateral, isolated, amygdala damage and showed no fear in typical fear assessments.
Learned fear

  • Classical conditioning: Pairing of:

    • Conditioned stimulus (CS) – e.g. A tone or a light
    • Unconditioned stimulus (US) e.g. a shock trains animals to respond to the CS in the absence of the US

  • You can use this paradigm to determine which brain regions are critical to the ability to learn new fear associations

  • Rodents often freeze in response to danger signals.

  • Lesion studies in rodents suggest that the amygdala is critical for the learning and expression of learned fear

In Fear Learning
  • The basolateral nuclei of the amygdala integrate sensory information from multiple sensory modalities.
  • The central nucleus of the amygdala sends outputs to stimulate a behavioral reaction as well as autonomic and emotional experiences
  • Most modern view is that complex circuits work together to generate complex behaviors like fear. The amygdala is a core ‘node’ in this network, But also works with the prefrontal cortex, hippocampus, thalamus, sensory cortices, etc. to generate or inhibit fear behaviors depending on context.

Ch. 22: Neurobiology of Mental Illness

  • Anxiety Disorders
  • Affective Disorders (Depression, Bipolar Disorder)
  • Schizophrenia

Psychosocial Approaches to Mental Illness

  • Views the mind and body as separate (Descartes’ Mind-Body Dualism).
    • Body disorders as physiological disorders.
    • Mental disorders as mental deficiencies (of willpower, morality, etc.).
  • Psychoanalysis (Sigmund Freud): Mental illness arises from conscious and unconscious elements of the psyche in conflict.
  • Behaviorism (B.F. Skinner): Mental illness is a result of maladaptive learned behaviors

Biological Approaches to Mental Illness

  • Mental and physical illness are both physiological and can be understood in terms of biological processes Mental illnesses are brain disorders caused by changes in the function of neurons/neural circuits (and glial cells!)
  • Understanding the neurobiology of the disorder allows us to develop better biomarkers for intervention and therapeutic targets

Diagnosing Mental Illness

  • Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5)
  • Diagnoses are based on symptoms and severity of impairment

Difficulties.

  • Diagnosed based on symptoms not etiology or biomarkers.
  • Symptoms can vary between people.
  • Same diagnosis can have many different causes.
  • No clear genetic basis and/or many genes implicated.
  • Modeling complex neuropsychiatric disorders in animals is basically impossible.
Mental Illnesses are BRAIN Disorders
  • We can’t treat brain disease like we do heart disease until we call it what it is!

Anxiety

  • Inappropriate expression of fear

  • Panic disorder Frequent panic attacks consisting of discrete periods with the sudden onset of intense apprehension, fearfulness, or terror, often associated with feelings of impending doom

  • Agoraphobia Anxiety about, or the avoidance of, places or situations from which escape might be difficult or embarrassing, or in which help may not be available in the event of a panic attack

  • Generalized Anxiety Disorder At least 6 months of persistent and excessive anxiety and worry

  • Specific phobias Clinically significant anxiety provoked by exposure to a specific feared object or situation, often leading to avoidance behavior

  • Social phobia Clinically significant anxiety provoked by exposure to certain types of social or performance situations, often leading to avoidance behavior

Related Disorders

  • Post-Traumatic Stress Disorder (PTSD).
  • Obsessive-Compulsive Disorder (OCD).

Biology of Anxiety

  • Fear is normally evoked by threatening stimuli - stressors
  • Anxiety = fear when stressor is not present or is not immediately threatening
  • HPA axis activation – vigilance, arousal, avoidance behavior, etc.
  • CRH(/F) – Corticotropin Releasing Hormone/Factor.
    • In mice, CRH overexpression increases anxiety-like behaviors.
    • CRH receptor knock-out mice exhibit less anxiety-like behavior
  • The amygdala, hippocampus, and frontal cortex regulate activity of the HPA axis
    • Amygdala activation increases HPA & diminishes inhibitory feedback from hippocampus.
    • Prefrontal and cingulate cortices also send top-down projections to modulate activity in these regions!

Anxiety treatments

  • Address symptoms not causes Psychotherapy – (and exposure therapy) fear has a large learned component – so this can be very effective at reprogramming learned associations
  • Anxiolytic Medications – Benzodiazapines and Selective serotonin reuptake inhibitors (SSRIs)
  • Benzodiazapines (Valium, Klonopin) - bind to a different site on the GABAA receptor and make it easier for GABA binding to open the channel and induce inhibition
    • Used for the treatment of ACUTE anxiety.
  • Selective serotonin reuptake inhibitors (SSRIs) - Block serotonin from being re-uptaken (cleared) from the synaptic cleft – MORE SEROTONIN in the synapse AND Serotonin may increase glucocorticoid receptors in the hippocampus… more inhibitory feedback for the HPA axis
    • SSRIs are not acute acting drugs – takes ~ a month for it to change overall serotonin tone and behavior So not useful for treating panic attacks acutely

SSRI

  • Normal Function: Released serotonin binds to postsynaptic receptors and is cleared by reuptake into the presynaptic terminal.
  • With drug present: Blocked reuptake increases serotonin in the synapse and postsynaptic signaling.

Affective Disorders

  • Major Depressive Disorder (MDD) – most common mood disorder 6% of the population every year
  • Bipolar Disorder (Manic-depressive Disorder)– Periods of mania intermixed with periods of depression
  • Depressive Symptoms: Depressed mood, Changes in appetite, Changes in sleep, Fatigue, Feelings of worthlessness or guilt, Inability to concentrate, Recurrent thoughts of death
  • Manic Symptoms: Inflated self-esteem & grandiosity, Increased talkativeness, Decreased need for sleep, Racing thoughts, Distractibility and Increased goal directed activity

Monoamine Hypothesis

  • Depression results from a deficit in one of the diffuse neuromodulatory systems.
  • BUT… too simplistic.

Stress-Diathesis Hypothesis

  • Diathesis= predisposition for a disease; can be due to genetics or previous experience
  • Early life stress – Abuse, neglect, trauma, etc. - is a risk factor for depression
  • Depression is associated with hyperactivity of the HPA axis: Elevated CRH in cerebrospinal fluid & Elevated blood cortisol
  • Early life experience has a profound impact on the HPA axis- and glucocorticoid receptor (GR) number in the brain
  • Does diminished GR /feedback play a role in depression?? SSRIs increase GR in the hippocampus and cortex!

Prefrontal Cortex and Depression

  • Damage to the vmPFC show very low levels of depression
  • Damage to dorsolateral PFC = the opposite – makes depressive symptoms worse
  • Anterior Cingulate Cortex is hyperactive in depression, involved in rumination/recursive thoughts
Depression Treatments
  • Deep Brain Stimulation of Area 25 (subcallosal cingulate cortex and depression): Initial responses of patients after 2-3 pulses
    • "the tension is gone"
    • "I'm not longer drowning"
    • "I'm out of the hole"
    • "the room is brighter"
    • "I feel lighter"
    • "I feel like cleaning"
Neuroinflammation and Depression
  • Depression and inflammation are linked in some patients, and anti-inflammatory drugs have been effective in reducing depressive symptoms only in patients with elevated cytokines at baseline
Lithium
  • An element effective at treating Bipolar disorder. It messes with several qPCR signaling cascades, but we really don’t understand why it is so effective in treating Bipolar Disorder

Memory Systems

  • Learning = The acquisition of new information and skills Memory = Retention of learned information

  • Memories are classified based on:

    • Time course: working memory vs. long-term memory
    • Type of information stored: declarative vs. nondeclarative
    • Sensory memory (seconds) Short-term memory (minutes) Intermediate-term memory (hours to days) Long-term memory (hours to lifetime)

  • Explicit/Declarative memory: Facts and events (Medial temporal lobe; diencephalon)

    • Semantic
    • Episodic

  • Implicit/Nondeclarative memory : Procedural memory: skills and habits (Striatum), Classical conditioning: Skeletal musculature (Cerebellum) and Emotional responses (Amygdala)

  • Amnesia = severe loss of memory and/or the ability to learn

    • Retrograde amnesia: Memory loss for events that occurred prior to a trauma
    • Anterograde amnesia: Inability to form new memories after a trauma

Systems

  • Working memory Prefrontal Cortex
  • Nondeclarative Memory cerebellum and amygdala
  • Declarative Memory human hippocampus
  • Working Memory Digit Span = the number of random numbers a person can read back after hearing a list read aloud – used as a measure of working memory …. Most people = 7 +/- 2
  • Lesions/damage to prefrontal cortex have trouble with working memory. Delayed Response Task= test of working memory in monkeys

Nondeclarative Memory

  • Procedural memory: knowing how to do things e.g. riding a bike, playing the violin - The Striatum is very important for this In its simplest form = learning a motor response to a stimulus Nonassociative and associative learning

  • Nonassociative learning: Learning to change your response to a stimulus over time Habituation – learning to respond less strongly to the same stimulus over time vs. Sensitization – learning to respond more strongly to the same stimulus over time

  • Associative Learning: Learning about/forming associations between different stimuli and therefore changing your behavior

  • Classical (Pavlovian) Conditioning – associating a stimulus that evokes a natural response (unconditioned stimulus) with a second stimulus (conditioned stimulus) that doesn’t evoke a response on its’ own

  • Operant (Instrumental) Conditioning: Learning to associate a motor action with a meaningful outcome: i.e. pressing a lever to get food Rewards reinforce/increase behaviors. Punishment decreases behaviors

Amygdala in Fear Learning

  • The basolateral nuclei of the amygdala integrate sensory information from multiple sensory modalities
  • The central nucleus of the amygdala sends outputs to stimulate a behavioral reaction as well as autonomic and emotional experiences
Striatum
  • The striatum appears to be critical to habit formation Studies in rodents, primates, and humans suggest that the striatum is engaged in habit formation and damage to striatum impairs habit formation
  • Patients with Amnesia vs Parkinson’s disease tested on 2 tasks: 1) Task 1: Learn through feedback which cards predict weather patterns 2) Task 2: Recall factual information about the test (computer, experimenter, etc.)

Declarative Memory

  • Encoding episodic memories, faces, places, etc.
  • Donald Hebb (1949) Memory Engram = cell assembly/ set of simultaneously active neurons that encode a memory – i.e. memory trace
  • Consolidation = strengthening of these connection so that reactivation of only a few can reactivate the network

Patients

  • H.M had a medial temporal lobectomy that resulted in severe anterograde amnesia and moderate retrograde amnesia BUT No effect on procedural memory, intelligence, personality.
  • Hippocampal stimulation and recording evokes memory-like sensations
  • Place cells and grid cells in the hippocampus - Some neurons in the hippocampus have specificity for specific places: fire in one location but not another PLACE CELLS vs. Fire in many areas that form a grid (almost like coordinates) GRID CELLS
  • Building a Brain Neurulation: Ectoderm tissue becomes neural tissue
  • Maturation: Telencephalon becomes Early brain subdivisions mature into adult subdivisions
  • Steps to neural development
    • Neurogenesis – neurons are born Migration – neurons move to their final place in the brain Differentiation
      • Most new neurons are born 5wks5mths gestation
      • Except for 1-2 regions, those are all the neurons you have for the rest of your life!! Most new neurons are born 5wks5mths gestation These neural stem cells are called Radial Glial Cells Give rise to all those new neurons
    • Later, give rise to all astrocytes and oligodendrocytes
      • Provide scaffolding for new neurons to move to cortex
    • Differentiation – neurons differentiate into different types of neurons (interneurons, pyramidal neurons etc.) Maturation – neurons extend axons, form refine synaptic connections
  • The brain develops from the inside out New neurons stop in deeper layers of cortex first
  • Combination of: cell intrinsic factors (which genes are turned on vs. off; transcription factors) and cell extrinsic factors (environmental cues like chemicals from other cells). Pax6 = more rostral Emx2 = more caudal.
  • Neuronal differentiation Fasciculation with cell adhesion molecules (CAMs) Chemical cues from other cells both attract and repulse developing axons to lead them to specific points
  • Connections are OVER abundant and then refined into adulthood. Programmed cell death and synaptic elimination/circuit refinement occur over most of development Synaptic density peaks