Psych Exam 2 Flashcards

Research Methods I + II

What are the ways to image a brain?

• Computed Tomography (CT)

• Positron Emission Tomography (PET)

• Magnetic Resonance Imaging (MRI)

  • Functional Magnetic Resonance Imaging (fMRI)

• Also other methods in animal models!

Computed Tomography (CT)

• Series of x-rays are passed through the head

  • Beams are absorbed in different ways based on tissue density

• Helpful to look at basic brain structures

  • White (axons) vs. Gray (cell bodies) Matter

• Often used for diagnostics

Magnetic Resonance Imaging (MRI)

• More powerful (and expensive!) than a CT scan (looks at structure mainly)

  • Better resolution

  • Images taken from any plane

  • Uses magnetism instead

• Functional MRI (fMRI) also looks at function

  • Change in brain metabolism during cognitive task

  • BOLD signal (tracks changes of oxygenated vs. deoxygenated blood)

BOLD (Blood Oxygen Level Dependent) Signal

• Used as an indirect measure of neural activity in an fMRI by tracking changes in blood oxygenation

  • a surplus of oxygen-rich blood goes to active brain areas (b/c they consume oxygen)

  • oxygen-rich blood has a brighter magnetic appearance, whereas oxygen-depleted blood has a darker magnetic appearance

Positron Emission Tomography (PET)

• Patient receives a radioactive tracer molecule

• Areas will absorb the substance if it uses it

• “Positrons” are released from area and collides with electrons

• Resulting gamma waves detected in scanner

• Note: a lot of radioactive exposure

Can also look at brains post-mortem (after death) - Histology, Nissl + Golgi Stains

• Histology is commonly used to look at anatomical structures within biological tissue

  • Gross Anatomy = big picture

  • Microscopic Anatomy = small (histology is microanatomy)

• Nissl stains use basic dyes to identify structures rich in RNA

• Golgi stains use silver (reveals the entire neuron structure)

Post-Mortem Brain Research (cont.)

• Immunohistochemistry: to visualize the location of proteins using antibodies (antibodies bind to proteins)

  • Can use fluorescent molecules to look at many simultaneously

• In-situ hybridization: to look at mRNA location in tissues using a labeled nucleic acid probe

  • Which gene is ON (epigenetics)

What if we want to assess neural activity in a different way?

• Electroencephalogram (EEG)

  • Measure electric fields as a result of active groups of neurons

  • Correlate activity to behavior

• Magnetoencephalogram (MEG)

  • Tiny magnetic fields are created by active groups of neurons

  • Excellent temporal resolution (precise timing)

  • Also for brain activity

Pre-clinical Models Can be Used to Record From Deep Brain Structures

• Stereotaxic surgery:

  • Targeting a brain region for precise placement of wires (electrode) or cannula for drug delivery

• Uses brain atlas for coordinate systems (helps guide stereotaxic surgery)

  • We have these for humans too!

What about manipulating the brain?

• We’ve already seen TMS (transcranial magnetic stimulation) with the somatomotor example!

  • Can also use direct (tDCS) or alternating (tACS) current instead of magnetism

• Deep Brain Stimulation (DBS) as an extreme measure

  • For “Treatment-resistant” patients (ex: severe depression)

  • Human stereotaxic surgery

More Sophisticated Research Methods in Animals

• Optogenetics: Use of lightsensitive proteins (opsins) to activate or inhibit neural activity (injected into a specific area of the brain)

• What do these proteins remind you of??? (ion channels - opsins are essentially light-gated ion channels)

  • Channelrhodopsin = excites neurons (reacts to blue light)

  • Halorhodopsins = inhibit neurons (reacts to yellow/orange light)

• Superior temporal resolution (superior time precision - real time reactions)

Necessity vs. Sufficiency

• Necessity

  • An event/trait cannot occur/exist without a necessary factor - “loss of function” experiments

• Sufficiency

  • Presence of a sufficient factor triggers or guarantees outcome when it is normally absent - “gain of function” experiments

Additional Sophisticated Techniques in Animals

• Chemogenetics: use of “Designer Receptors Exclusively Activated by Designer Drugs” (DREADDs) (scientists place these receptors onto specific brain cells)

  • These are G-protein coupled receptors (What do those do? - G protein is activated to open ion channels or do other cell stuff)

• DREADDs activated by specific compounds (CNO) to either excite or inhibit cells

• Longer-lasting

How do you think like a scientist? - Scientific Method

• Make observations in the world

• Question about the “why” and the “how”

• Formulate a hypothesis about a mechanism

• Design and execute an experiment

• Collect and interpret data

• Conclusions & implications

*Much of this is summarized in an abstract*

3 Approaches to Study the Biological Basis of Behavior

1. Somatic Intervention: Manipulating the body (brain) changes behavior

2. Behavioral Intervention: Manipulating behavior changes the body (brain)

3. Correlation: Measure how closely the body and behavior covary

Experiments Need to be Carefully Designed

• Control Group: They do not experience any alteration or treatment

  • AKA: “Vehicle”, “Placebo”, “Sham”

• Between-Subject: separate experimental and control groups

• Within-Subject: Same set of subjects with alternating treatment

What are Variables?

• Independent Variable: The structure or function that is being altered

  • What you manipulate

• Dependent Variable: The response that is being measured

• Nuisance Variable: Other factors that could influence results

Understanding the Brain Through Reductionism + Why Use Animal Models (3 R’s)

• Reductionism: Breaking a system down into its smaller parts in order to understand it

• Many features of the brain are evolutionarily conserved

  • Shared features w/ animals

  • Use of animal models due to ethical and technical limitations for behavioral neuroscience in humans (example: genetic mouse model of ASD)

    • Use of the 3 R’s in animal research: Replace, Reduce, Refine

Example: Genetic Mouse Model of ASD

• Identified human genes first

  • Shank3, Fmr1, Chd8

• A gene is inserted into a mouse genome

  • Mouse will develop with the gene

  • OR gene is knocked out

• Observe the mouse behavior

  • Excessive grooming, social anxiety

  • “ASD-like”

Data Can Take Different Forms (Qualitative vs. Quantitative)

• Qualitative and/or Quantitative

  • Qualitative = descriptive, text-based (e.g., survey responses)

  • Quantitative = measured or expressed in numbers

• Prioritize quantitative measures for statistical comparisons

  • Experimental vs. Control

  • Can still have qualitative measures depending on the experiment

What Are Some Quantitative Behavioral Metrics?

• Duration = amount or % time engaging in a task/behavior

• Rate = frequency or # of behaviors

• Intensity = strength/magnitude of the behavioral response

• Speed = how quickly or slowly does the behavior progress

• Latency = Time prior to initiative response

• Error = # of mistakes made

Data Visualization: Figures (Experimental Protocol + Representative Data)

• Experimental Protocol

  • Overview of the experiment design

  • Timelines

  • Experimental groups

• Representative Data

  • “Punchline” figure

  • Main differences

Data Visualization: Figures (Combined Data + Summary Figure)

• Combined Data

  • Differences across groups

  • Highlights statistical differences

  • Bar plots, line plots, histogram

• Summary Figure

  • Big picture ideas from the study

Hormones

What are hormones?

• Chemicals that travel via the bloodstream to act on target organs or tissues

  • Most secreted from endocrine glands

  • Endocrine system is distributed throughout the body

• Some neurons can secrete/release hormones

  • CRH neurons in the hypothalamus

Difference Between Hormones and NT Communication

• Synaptic transmission (chemical)

  • Precise locations

  • Affects nearby cells if they have proper receptors

  • NTs don’t usually travel far (20- 40 nm)

  • Rapid, but short-lasting

• Hormonal communication (primarily in bloodstream)

  • Spreads throughout the body

  • May travel over 1 meter!

  • Affects any type of cell if they have proper receptors

  • Messages are slower, but long-lasting

Hormones are Released in Different Ways

• Can affect multiple or only one target organ

• Neurocrine: released by presynaptic cell, binds to receptors on postsynaptic cell

• Endocrine: secreted into the bloodstream, travels throughout the body, affects target tissues with receptors

• Neuroendocrine: released into the bloodstream following neurotransmitter communication

Many Chemical Signals - Pheromones + Allomones

• Pheromones: Chemicals released from the body to affect others of the same species

• Allomones: Chemicals released from the body to affect different species

Hormones are Classified By Structure

• Peptide hormone: small proteins made of a string of amino acids

• Amine hormone: modified version of a single amino acid; also called monoamine hormone

• Steroid hormone: derived from cholesterol and are made of four rings of carbon atoms

Pepride + Amine vs. Steroid Hormones

• Peptide and Amine hormones will bind directly to GPCRs

  • Either excitatory or inhibitory

  • Acts within seconds to minutes

• Steroid hormones are lipid-soluble and can pass through cell membrane

  • “Selective permeability”

  • Intracellular receptors

  • Acts within hours to days

  • Can be permanent or transient (temporary)

Pituitary Gland = Major Hormone Center (Anterior Pituitary vs. Posterior Pituitary)

• Under control of the hypothalamus

• Hypothalamus sends efferent projections out towards the pituitary gland

• Anterior Pituitary: Regulates other endocrine glands—synthesizes and releases different hormones (tropic hormones)

  • Releasing hormones from the hypothalamus triggers anterior pituitary to make new (tropic) hormones, which bind to new targets

• Posterior Pituitary: Does not synthesize hormones, instead is a funnel for neuroendocrine cells to send axons from hypothalamus

  • Transports Oxytocin + Vasopressin

Anterior Pituitary Hormone Processes/Examples

• Hypothalamus creates releasing hormones, which travel to the anterior pituitary

• The anterior pituitary then creates tropic hormones that regulate endocrine glands throughout the body

  • Ex: CRH (in hypothalamus) —> ACTH (in anterior pituitary) —> adrenal cortex —> corticosteroids

  • FLAT PEG - acronym for anterior pituitary hormones

    • Follicle Stimulating Hormone

    • Luteinizing Hormone

    • ACTH

    • Thyroid

    • Prolactin

    • Endorphins

    • Growth Hormone

Oxytocin (posterior pituitary)

• Oxytocin-producing neurons in the hypothalamus release from posterior pituitary

• Can be used by both brain and body

  • Amygdala, Nucleus Accumbens (NAc), Prefrontal Cortex (PFC), Raphe Nuclei

• “Milk Letdown Reflex” (for breast feeding)

• Maternal & social behavior

How do Hormones Relate to Maternal Experiments with Rats?

Vasopressin (posterior pituitary)

• Hypothalamus will stimulate “thirst” and release vasopressin through the posterior pituitary

• Important hormone for regulating blood volume and salt concentration

• Direct action on kidneys for water retention and reduces urine production

• Also important for social behavior

ACTH (anterior pituitary)

• Adrenocorticotropic hormone

  • Major player within the HPA axis (hypothalamic-pituitary-adrenal axis: system for body’s stress response/management)

• Hypothalamus will secrete corticotropin-releasing hormone

  • This goes into the anterior pituitary gland

• ACTH released by anterior pituitary and is used in the adrenal glands

• ACTH then causes release of cortisol (stress hormone)

Gonad Hormones (anterior pituitary)

• Gonadotropin-releasing hormone (GnRH) cells in the hypothalamus will travel to the anterior pituitary

• Release one or both that act on gonads

  • Follicle-stimulating hormone (FSH): stimulates growth of follicles or sperm production

  • Luteinizing hormone (LH): Egg release or testosterone production

Other Anterior Hormones (Thyroid-Stimulating, Prolactin, Growth Hormone)

• Thyroid-stimulating hormone (TSH): will stimulate the production of T3 and T4

  • Low = thyroid needs to work harder!

  • High = thyroid needs slow down!

• Prolactin: breast development and milk production

• Growth hormone (GH): physical growth, repair

Negative Feedback

• We cannot produce hormones all the time!

• Hormone output finds its way back to the hypothalamus

  • Enough hormones are bound to trigger a biological response

  • Cue to stop producing more hormones

• Process can start again

Drugs and the Brain I + II

Drugs Act on Receptors

• Drug = a chemical substance, when taken into the body, alters the structure or function of the body in some way

  • Exogenous (from outside the body)

  • Psychoactive drugs have effects on the brain and nervous system

• Drugs can bind to receptors (ionotropic or metabotropic)

• Mimic NTs - Agonist

• Prevents receptor from working - Antagonist

  • Antagonists can be either competitive (binds to same site as NT) or noncompetitive (binds to a different site as NT)

Four Main Routes of Drug Administration (in order of speed)

• Injection: bypasses the digestive tract

  • Intravenous: in bloodstream (fastest)

  • Intramuscularly: muscles (2nd fastest)

  • Subcutaneous: under the skin (slowest)

• Ingestion: Oral route

• Inhalation: Absorbed in capillaries in the lungs

• Absorption: Skin contact

Blood Brain Barrier (BBB)

• Prevents most molecules from crossing into the brain from the body (barrier lines blood vessels in the brain)

• Astrocytes help maintain structures

• Some things can pass through freely

  • Lipid-soluble molecules

  • Small molecules

  • Transporter proteins shuttle things through

Pharmacokinetics vs. Pharmacodynamics

Pharmacokinetics

• What the body does to the drugs

• All factors from drug entry to body, movement within body, to exit from body

• Tells us about a drug’s bioavailability

  • How much drug is free to act on the body’s targets

Pharmacodynamics

• What the drugs do to the body

• All processes related to ligand-receptor binding

• Tells us about a drug’s mechanism of action

• How the drug exerts effects on brain and behavior

Drugs are Broken Down Eventually…

• Cleared from the brain by Glymphatic system or the BBB

  • CSF + glia + blood vessels

• The liver is the primary source of metabolism via biotransformation (body altering a compound)

  • Break down into smaller parts

• Kidneys are the primary source of excretion

• Small amounts can also be excreted elsewhere

A Drug’s Effects Depend On…

• Bioavailability: How much drug is in circulation (to act on targets)

• Where it binds in the brain

• Affinity: how strongly the drug binds to a receptor

• Efficacy: the ability of a ligand (drug) to (in)activate a receptor

• Examine a dose-response curve

  • ED50: Dose needed for half of the maximal effect (lower ED 50 = better binding affinity)

  • Want to maximize biological effects while minimizing a dose

Efficacy vs. Potency

• Maximal Efficacy = maximal extent in which effects appear in clinical populations (maximum effect a drug can achieve)

  • Graph plateau shows this

• Potency = amount of drug required to produce a biological effect

• Want to minimize dose while maximizing effects

Therapeutic Index

• Separation between useful doses and dangerous doses

• Toxic Dose (TD50): 50% animals show signs of toxicity

• Lethal Dose (LD50): Fatality of 50% animals

• TI = LD50 - ED50

Substance Use Disorder

• Patterns of symptoms caused by using a substance that an individual continues taking, despite negative effects

  • Using more of a substance than intended or using it longer than you’re meant to

  • Trying to cut down or stop, but being unable to

  • Experiencing intense cravings or urges to use the substance

  • Need more of the substance to get the desired effect (tolerance)

  • Developing withdrawal symptoms when not using substance

  • Neglecting responsibilities at work, home, or school because of substance use

  • Using substances in risky settings that put one in danger

  • Continuing use despite changes in physical or mental health

Withdrawal, Dependence, Relapse

• Withdrawal: When drug use is terminated and symptoms are the opposite of the drug’s effects

• Dependence: Body has adapted to the drug and requires it to function normally

  • Severity depends on the type of drug and pattern of use

  • Shift from impulsive to compulsive behavior

• Relapse: Return to active drug use after a period of successful abstinence or recovery

Presynaptic Mechanisms (of Drugs)

• Neurotransmitter production

  • Enzymes that make NTs (1)

  • Transport materials down microtubules (2)

  • Neurotransmitter storage (3)

• NT Release (7)

  • Bind to ion channels (4, 5)

  • Pre-synaptic receptors (6)

• NT clearance

  • Re-uptake proteins (8)

  • Degradation (9)

Neuroscience IRL: Caffeinated Drinks

• Blocks autoreceptors on the presynaptic neuron

  • Feedback mechanisms for neurotransmitter release

  • Normally adenosine binds there!

• Prevents adenosine from activating sleep-promoting pathways

• Can still become dependent and experience withdrawal

Postsynaptic Mechanisms

• Receptors

  • Antagonists (1) prevent receptor from working

  • Agonists (2) activate the receptors

• Other intracellular processes

  • Receptor regulation (3)

  • Second messenger systems (4) - ex: GPCRs

Receptor Regulation

• Target tissues can increase or decrease sensitivity to a drug by regulation of the # of receptors

• Down-regulation: fewer receptors

• Up-regulation: more receptors

The “Reward System”

• Mesolimbocortical pathway (VTA → Nucleus Accumbens) of dopamine (for motivation + reward)

• Many addictive substances and behaviors cause dopamine release into the nucleus accumbens

• Research from the lab shows the importance of this pathway

  • Necessity and Sufficiency

• Neuroscience IRL: social media algorithms

Opioids - examples, theraputic uses, addiction potential

• Examples: Morphine (Schedule II), Fentanyl (Schedule II), Carfentanil (Schedule II), Oxycodone (Schedule II) • Heroin (Schedule I)

• Therapeutic uses: Pain management, Anesthesia, Cough suppressant (back in the day)

• Epidemic in the US

• High addiction potential

Opioids (cont.) - effects, administration, mechanism of action, withdrawal, therapeutic uses, withdrawal, treatment for addiction

• Acute effects: Euphoria, relaxation, pain relief, respiratory depression, nausea

  • Can cause coma and death

• Administration through either ingestion (pills) or IV injection

• Bind to dedicated opioid receptors

  • Receptor activation will then suppress GABA production (inhibiting an inhibitor)

  • Indirect release of dopamine

• Withdrawal is brutal

  • Muscle pain, diarrhea, vomiting, nausea, sweating, anxiety, high heart rate, abdominal pain, insomnia

  • Desire to avoid adds motivation to use

• Treatment for addiction

  • Drugs that directly block opioid receptors (Narcan, Naltrexone)

  • Medication-assisted treatment (Methadone, buprenorphine)

  • Harm-reduction strategies (Narcan, test strips, needle disposal/exchange programs)

  • Cognitive behavioral therapy

Cannabinoids - examples, theraputic uses, addiction potential, acute effects, mechanism of action, withdrawal

• Examples: THC (Schedule I), Dronabinol (Schedule II), CBD (not considered a controlled substance

• Therapeutic uses: FDA-approved epilepsy treatment (CBD and dronabinol), relieve nausea & vomiting, chronic pain management

• Smoking, eating, topicals

• Addiction potential: mild to moderate

• Acute effects:

  • Relaxation, mood alterations, increased appetite, impaired judgment, motor deficits, impulsivity

  • High doses cause hallucinations, synesthesia, paranoia, confusion, respiratory problems, cognitive decline, short-term memory loss, heart attacks

  • No evidence suggesting brain damage

• Mechanism of Action:

  • Binds to the endogenous cannabinoid receptors - Anandamide (2-AG) (blocks Ca2+ channels), CB1 & CB2, Increase firing of dopamine neurons*

• Withdrawal includes irritability, insomnia, decreased appetite and mild anxiety

Stimulants - examples, therapeutic uses, acute effects, addiction potential, withdrawal

• Examples: Caffeine (not a controlled substance), Nicotine (not a controlled substance), Cocaine (Schedule II), Amphetamines/ Methamphetamines (such as Adderall, Ritalin, vyvance (Schedule II)) (not a controlled substance)

• Smoking, snorted, ingestion

• Therapeutic uses: ADHD treatment, Narcolepsy, Local anesthetic (rare; cocaine)

• Acute effects: Increased alertness & focus, Elevated heart-rate/blood pressure, Decreased appetite, High doses induce neurotoxicity, psychosis, heart strain, stroke risk, insomnia, anxiety

• Strong addictive potential

• Withdrawal includes headaches, fatigue, depression, sleep disturbances, irritability, anxiety, difficulty concentrating, cravings

Stimulants Mechanism of Action - Nicotine, Cocaine, Amphetamines

• Nicotine

  • Binds to nicotinic acetylcholine receptors (some of which are found on dopamine neurons) (ionotropic)

  • Dopamine neurons will become active and release dopamine

  • Neuroscience IRL: nicotine and memory

• Cocaine

  • Indirect agonist: blocks dopamine reuptake proteins

  • Dopamine stays in the synaptic cleft longer

• Amphetamines

  • Indirect agonist: Reverses the direction of the transport proteins

  • Pumps more dopamine OUT of the cell

Alcohol - examples, acute effects, mechanism

• Examples: beer, wine, liquor

• High potential for misuse

• No therapeutic uses, just recreational

• Effects are considered biphasic

  • Initial stimulant, then depressant

• Acute effects:

  • Relaxation, lower inhibition, motor impairment

  • High doses lead to liver disease, cardiovascular problems, brain atrophy, dependence

• Mechanism:

  • “Depressant” ≠ mood

  • GABA agonist (mimics GABA - inhibitory)

  • Glutamate antagonist (NMDA - blocks ionotropic receptor - blocks excitatory)

Alcohol - withdrawal, widely consumed, treatment

• Withdrawal is severe

  • 5-6 hrs post-drinking: tremors, nausea, sweating, vomiting, etc.

  • 15-30 hrs: convulsive activity

  • 24-48 hrs: Delirium tremens may last 3-4 days

• Most widely consumed psychoactive susbtance

  • • ~55% heritable alcohol use disorder

  • Effects almost every tissue in the body

• Treatments vary

  • Benzodiazepines for withdrawal

  • Naltrexone, acamprosate, disulfiram to curb drinking behavior

  • Cognitive Behavioral Therapy

• Neuroscience IRL: alcohol + memory (brain cannot convert short term memories into long term memories)

Psychedelics - examples, therapeutic research, acute/long term effects, withdrawal, addictive potential

• Examples: LSD (Schedule I), Mescaline (Schedule I), Psilocybin (Schedule I), MDMA (Schedule I)

• Mode: Ingestion

• Current therapeutic research:

  • LSD = microdosing for anxiety, depression, substance use disorders

  • Mescaline = substance use disorders

  • Psilocybin = substance use disorders, PTSD, depression

  • MDMA = PTSD

• Acute effects: Vivid visual hallucinations, slowing the sense of time, disassociation, strong emotional reactions, disruption of logical thought

  • Long-term effects include “bad trips”, dehydration, serotonin toxicity

• Withdrawal includes depression and mood swings

• Low addictive potential

Psychedelics Mechanisms of Action - LSD + Psilosybin and MDMA

• LSD & psilocybin

  • Binds to serotonin receptors to activate them

  • Increased effects

• MDMA

  • Enters neurons that release either serotonin or dopamine

  • Blocks reuptake

  • Serotonin and dopamine remain in the synaptic cleft

Emotions

• Subjective mental state that is accompanied by distinctive behaviors and physiological changes

  • Overt behaviors

  • Motivational states

  • Physiological arousal

  • Emotional dysregulation - hallmark of many psychopathologies

Why Are Emotions a Good Thing?

• Evolutionary adaptations

  • Enhance the ability to experience and evaluate environment cues

  • Can coordinate behavioral responses to solve problems

• Central to social communication

  • Enhance the abilities to interact and communicate with others in appropriate ways

Competing Viewpoints on What Comes First - emotion, physiological arousal, cognitive attribution

• Folk psychology: emotion —> physiological reaction

• James-Lange Theory:

  • physiological reaction —> emotion

• Cannon-Bard Theory:

  • physiological reaction and emotion occur at the same time

• Schachter + Singer Theory:

  • physiological reaction —> cognitive appraisal/assessment —> emotion

Are There “Core” Emotions?

• There is no unifying list of emotions, but general agreement on six

  • Fear

  • Anger

  • Surprise

  • Disgust

  • Happiness

  • Sadness

• Intensity depends on level of arousal

The Limbic System (aka Papez Circuitry)

• Set of brain regions that link the cortex with the hypothalamus - important for emotions

• Structures:

  • Hypothalamus, Thalamus, Cingulate Cortex, Hippocampus, Amygdala, Fornix

Amygdala = Seat of Emotion

• Important for linking valence to memory

  • Valence: Is a memory good or bad?

• Lesions (damage) produce deficits in emotional processing

  • Decreased fear and aggression

  • Decreased facial expressions and vocalization with fear

  • Poor visual recognition

  • Lack of social restraint

  • Hyperorality

  • Klüver-Bucy syndrome

• Stimulation will increase vigilance, anxiety, fear, and aggression

  • Can do this either electrically (DBS) or with optogenetics (animals only)

• fMRI imaging studies reveal greater activation in amygdala BOLD signal in fearful faces than in neutral ones (more oxygenated blood in amygdala w/ fearful faces)

Patient SM - “The woman who was never afraid” (destroyed amygdala)

• Most common symptom: Inability to recognize fear in facial expressions

• Low self-reporting score on watching film clips

• Abnormal eye movement in Patient S.M.

Different Patterns of Brain Activation Across Emotions

• Studies use fMRI to study patterns of activation during sadness, happiness, anger, and fear

• Both Limbic and non-Limbic areas

  • Insula (purple)

  • Cingulate Cortex (both green and blue)

  • Prefrontal Cortex (yellow)

  • Amygdala (red)

• Network = multiple brain regions working together

Fear Can Also Be Learned

• “Fear Conditioning”

  • CS = Conditioned Stimulus (ex: tone/bell)

  • CR = Conditioned Response (ex: fear)

  • US = Unconditioned Stimulus (ex: electrical shock)

  • UR = Unconditioned Response (ex: fear)

Stress

Stress = A Multidimensional Concept

• Stressful stimulus, stress processing, stress response

• Acute stress seen as adaptive

  • Increase alertness, focus and motivation

  • Stimulate immune system

  • Stimulate neuronal & astrocyte growth (shown in mice)

  • Positively impacts memory

  • Increases resilience

• Neuroscience IRL: public speaking (tied to stress hormone)

Reappraising “Stress is Good”

• Reappraising (reinterpret its meaning) a stressful experience so that it is seen as helpful and controllable has been shown to improve immediate cognitive, physiological, and behavioral stress responses

Stress on the Body

• Activation of two hormonal systems (HPA axis + Sympathetic nervous system) to trigger release of:

  • Glucocorticoids (cortisol) from the adrenal glands

  • Epinephrine (adrenaline) and norepinephrine (noradrenaline) from the adrenal glands

• Hormones cause the physiological responses of stress

  • Beta-blockers prevent these during stress!

Stress on the Body - Cortisol + Immune System

• Cortisol suppresses the immune system

  • Short-term defense mechanism allowing body resources to be used elsewhere

  • Stress does not make you sick, but makes you more likely to get the diseases that make you sick

• Once stress levels decrease, immune system back on

Stress on the Body - Long-Term Stress

• Our stress response system is not built for chronic stress!!

• Long-term stress has devastating consequences

  • Extreme trauma/stress = PTSD

  • Physical health decline

  • Some signs of neurodegeneration

  • In the wild, animals die under prolonged stress

• Connect to Maternal Experiments with Rats Again

  • Stressed mom —> epigenetic changes in developing mice (methylation, high stress hormone levels and anxiety levels, cannot adapt to cortisol in the same way)

Neuropsychiatric Disorders I and II

Neuropsychiatric Disorders are Highly Prevalent

• ~15-50% of the global population reports some psychiatric symptoms at some point in life

• ~19% of US adults experience symptoms each year

• Can occur in any age and in any individuals

  • Rates vary across demographics

Anxiety is Slightly Different From Stress

• Both trigger sympathetic nervous system

• Some shared symptoms

  • Difficulty sleeping, focusing

  • Fast heart rate, breathing

  • Muscle tension & headaches

• Anxiety = Characterized by fear and the occurrence of an inappropriate stress response, even when the stress is not there

Types of Anxiety Disorders

• Generalized Anxiety Disorder: persistent excessive anxiety, worry

• Social Anxiety Disorder: Fear and avoidance of negative public scrutiny, public embarrassment, humiliation or social interaction

• PTSD: Anxiety disorder that results from traumatic experience

• Panic Disorder: Recurrent attacks of intense fearfulness

• Phobic Disorder: Irrational fears centered on an object, activity, or situation that a person avoids

HPA Axis Revisisted in Anxiety

• There is a genetic predisposition to many anxiety disorders

  • Also, environmental factors play a huge role!

• Stress response is triggered by fear and initiated in the hypothalamus

  • What stress hormone(s)? - CRH, ACTH, Corstisol

“Push-Pull” Regulation of the HPA Axis

• Too much amygdala activity stimulates inappropriate hypothalamus activity

• Too little hippocampal activity stimulates inappropriate hypothalamus activity

  • Normally helps with feedback regulation of the hypothalamus to stop cortisol production

  • Chronic cortisol will cause degeneration/lack of neurogenesis

Hippocampus = Also Affected by PTSD

• PTSD Symptoms

  • Intrusive re-experiencing of the trauma

  • Avoidance of stimuli associated with the trauma

  • Negative mood and cognitive capacity associated with the trauma

  • Excessive arousal and reactivity

• PTSD caused a reduced hippocampus size

  • Severity correlates with size (more severe, smaller size)

Animal Models: “PTSD-Like”

• Stress-Enhanced Fear Learning Paradigm

  • Slightly modified fear conditioning paradigm

  • One group of animals gets severe shock, the other does not

• Can look at behavioral and physiological responses

  • Freezing, Blood pressure (higher)

  • Neurogenesis impacted

  • Developmental consequences

Treatments for Anxiety Disorders

• Psychotherapy

  • Collaborative talk therapy

• Benzodiazepines are anxiolytic (reduces anxiety symptoms)

  • Acts on GABA-A (ionotropic) receptors to increase inhibitory activity (Cl- into cell + inhibits)

• Serotonin Agonists

  • SSRI = Selective Serotonin Reuptake Inhibitor

Extinction Learning

• Gradual weakening of the original conditioned response (CR) by re-exposure to the conditioned stimulus (CS)

  • Like exposure therapy

  • CS is no longer paired with the unconditioned stimulus (US)

• Repeated exposure of cue in “safer” contexts helps decrease the fear

  • Decreased freezing and blood pressure

Diagnosis With DSM 5

• Diagnostic and Statistical Manual 5th version

• 5 or more symptoms within a 2-week period to get depression diagnosis

  • Depressed mood (or irritability in children or adolescents) or anhedonia (cannot experience pleasure/joy)

  • Weight or appetite changes

  • Sleep disturbances

  • Psychomotor changes

  • Fatigue or slow energy

  • Concentration impairment

  • Suicidal ideation

What is an Affective Disorder?

• Disorder characterized by alterations in emotion or mood

• Major Depressive Disorder (MDD): Combination of debilitating symptoms

• Dysthymia: Lowered mood, but not as severe as MDD

• Bipolar Disorders: Periods of clinical depression alternated by extreme elation or mania

• Atypical Depression: Overeating, oversleeping, fatigue - Mood changes in response to events

• Psychotic Depression: Major depression along with loss of touch with reality

• Postpartum Depression (PPD): Depression after giving birth that outlasts the “baby blues”

• Premenstrual Dysphoric Disorder: Severe form of premenstrual syndrome with depression symptoms

• Seasonal Affective Disorder (SAD): Depression that occurs each year at the same time, usually winter months

Affective Disorders = Widespread

• ~7% of the US population has at least 1 depressive episode per year

• 2019: 15.2% major depressive episodes were between ages 18-25

• 20% of the population will have a depressive episode in their life

Risk Factors for Depression

• Heritable component

  • “Twin studies”: 60% concordance (identical), 20% concordance (fraternal)

• Many genes contribute to making a person susceptible

  • “Polygenic” condition

  • Serotonin production/release, HPA axis regulation

  • BDNF: brain derived neurotrophic factor (protein that helps with neurogenesis + neuroplasticity)

• Environmental factors also play a role (diet, substance abuse, etc.)

Alterations in Brain Structure + Function due to Depression

• Increased activation in frontal lobes during cognitive tasks

• Increased amygdala activation during emotional processing

• Decreased blood flow to brain areas implicated in attention

• Reduced hippocampal volume and activation during memory tasks

Depression Treatments

• Antidepressants

  • Take a long time to work (can take months)

  • Examples: SSRIs (prevents serotonin reuptake) and monoamine oxidase inhibitors (prevents NTs from being broken down into metabolites - prevents biotransformation)

• Spravato (Esketamine) - (antagonist for Glutamate NMDA receptors)

  • Nasal spray, works within hours

  • More potent version of ketamine

  • For treatment-resistant depression

• TMS, DBS (invasive)

  • Faster relief from symptoms

• Cognitive Behavioral Therapy

The Monoamine Hypothesis

• Monoamines = serotonin, norepinephrine, dopamine

• All drug classes to treat depression increase the level of monoamines that could be used in the synapse

• Mood is closely tied to the levels of released monoamines in the brain

  • Depression as a deficit of neurotransmitters

Mechanism of Action + Examples of Antidepressants (MAO Inhibitors, Tricyclics + Heterocyclics, SSRIs, 2nd Generation Antidepressants + Investigational Drugs)

The Monoamine Hypothesis: Evidence For and Against

• Evidence in Support

  • Drugs are successful in reducing depressive symptoms

  • Lower levels of serotonin metabolites have been found in CSF

  • Lower concentrations of serotonin and metabolites in postmortem brain tissue

  • Depletion of serotonin (tryptophan-free diet) worsens depressive state

• Evidence Against

  • Drugs increase serotonin levels immediately, but people don’t experience reduction in symptoms weeks later

  • Many people do not respond to drugs

  • Serotonin depletion does not induce depression in control subjects

  • Antidepressants do not elevate mood in control subjects

  • Increased suicide risk in children and teens that use SSRIs

Animal Models Used To Study Depression

• Sucrose Preference Test

• Tail Suspension Test

• Forced Swim Test