Psych 230 Exam 2

Hormones

Chemicals, secreted by a group of cells (i.e., gland), that travel through the bloodstream to act on targets

Endocrine Glands vs. Exocrine Glands

Endocrine Glands: Release hormones within the body

Exocrine Glands: Use ducts to secrete fluids such as tears and sweat outside the body

Endocrinology

The study of endocrine glands and their associated hormones

Ectocrine

A chemical substance released by an organism into the external environment that influence the behavior, growth, or development of other organisms (either of the same or different species)

1st Formal Experiment of Endocrinology; Conducted by Arnold Berthold in 1849

Essentially, his study used roosters to figure out how the testes influence physical traits and behavior.

Berthold divided six young male chickens into three groups:

• Group 1 (Undisturbed): No removal

  • Chickens had large red wattles and cockscombs; would mount and mate with hens readily; would fight one another and crow loudly

• Group 2 (Castration): He removed the testes completely

  • These chickens developed small cockscombs and wattles; weakly crowed; and showed no interest in hens or fighting other males

• Group 3 (Castration + Re-implantation): He removed the testes and immediately transplanted them back into the chicken’s own abdominal cavity, but as a different, disconnected site

  • Also was another group where testes were removed and transplanted into the abdominal cavity of different castrated chicken

  • Both of these groups developed normally into full roosters

Upon later dissection of the birds, Berthold discovered that the transplanted testes had reattached to the intestines and developed a completely new network of blood vessels, but they had no nerve connections to the rest of the body

• Because the transplanted organs worked without any connection to the nervous system, Berthold concluded that the testes must release a “secretory blood-borne product” directly into the bloodstream that acts on the entire organism

  • He didn’t isolate the chemical itself, but his work laid the foundational work for the eventual discovery of testosterone

Synaptic Communication

Involves chemical release into the synaptic cleft for action of the postsynaptic membrane

Endocrine Communication

A hormone is released into the bloodstream to act on target tissues

Neuroendocrine/ Neurosecretory Cells

Neurons that release hormones into the blood

Synaptic vs. Endocrine Communication

Synaptic Communication

• Travels only across a synaptic cleft to act on receptor

• Signal travels along a laid path (circuit)

• Very fast

Endocrine Communication

• Spreads anywhere throughout the body if there is blood supply; can act on cells with the appropriate receptor

• Relatively slow

Paracrine Function

The released chemical diffuses to nearby target cells (ex; synaptic transmission)

Autocrine Function

A released chemical acts on the releasing cell (ex; autoreceptors on neurons)

Pheromone Function

Hormones can be used to communicate between individuals of the same species; pheromones are released into the environment

Allomone Function

Allomones are chemicals released by one species to affect the behavior of different species

How do Hormones Act?

Hormones act by changing the probability or intensity of a behavior; Hormones don’t make you do anything

Reciprocal/ Bidirectional Relationship

• Hormones change behavior AND behavior changes hormones

Principles of Hormone Action

• A hormone may have multiple effects, and one behavior can be affected by several hormones

• Hormones often act in a pulsatile secretion pattern

• Hormones can interact with other hormones and change their effects

• Hormones can only affect cells with a receptor for that hormone

Multiplicity of Hormone Action

• Some hormones affect more than one target

• Some targets are affected by more than one hormone

Peptide Hormone (or Protein Hormone)

• Made up a string of amino acids

• Peptide hormones: only a few amino acids in lengths

• Protein hormones: larger ones (>50 amino acids)

• Can be stored within the cell (in vesicles)

• Large (can’t pass through cell membranes)

• Ex; oxytocin, insulin, leptin

Amine Hormones

• Derived from/modified amino acids, called monoamine hormones

• Two classes of these hormones affect behavior:

  • Indoleamines (ex; serotonin)

  • Catecholamines (epinephrine, dopamine)

• Thyroid hormones are also monomines, but they don’t affect behavior

Protein and Amine Hormone Action

• Protein and amine hormones bind to specific receptors embedded within the cell membrane and cause release of a second messenger, which brings about changes in cellular function

• This action is relatively fast (effects on order of ms to min)

Steroid Hormones

• Derived from cholesterol

• Most come from the adrenal glands and gonads

• Small and lipophilic (passes through cell membrane)

• Never stored

• Some require carrier proteins, or cofactors

• Ex; estrogens, androgens

Steroid Hormone Action

• Steroid hormones pass through the cell membrane and bind to receptors inside the cell

• The steroid-receptor complex binds to DNA in the nucleus and acts as a transcription factor, controlling gene expression and protein production -hence, effects are longer lasting

• This is relatively slow (effects usually on order of hours to days)

• Called: Genomic Action

• Some steroids can have alternative actions, as well:

  • Estradiol can have rapid, brief effect involving neuronal membrane receptors; this is called nongenomic action

• Neurosteroids: steroids made in the brain, including testosterone and estrogens

• Many steroid hormones are made by combining an enzyme with a different hormone

  • For example, aromatase is an enzyme that can convert testosterone into estrogens inside a cell (androgens like testosterone into estrogens like estradiol)

Some chemicals can act as both neurotransmitters AND hormones

• Depends on the cells that release them, and where they are released

• Ex; Serotonin

Feedback Systems

• Hormones are regulated by feedback systems

  • Negative Feedback: output feeds back and inhibits further secretion

    • Much more common in terms of hormone regulation

  • Positive Feedback: output feeds back and increases further secretion

Autocrine Negative Feedback Loops

Involves endocrine cells releasing a hormone whose presence feeds back on the endocrine cells

Target Cell Feedback

The hormone acts on its target cells and has a biological effect

• The biological effect is detected by the endocrine gland and further release is inhibited

Brain and Pituitary Regulation

• A more complex endocrine system involved the brain, usually the hypothalamus

• First, the hypothalamus uses “releasing hormones” to act on the anterior pituitary

• Then the pituitary released tropic hormones that affect other endocrine cells

• Negative feedback from the endocrine cells goes to both the pituitary and the hypothalamus

Hypothalamic-Pituitary Interactions

• The hypothalamic neuroendocrine cells that synthesize releasing hormones are influenced by:

  • Circulating messages, such as other hormones, blood sugar, and immune system products

  • Synaptic inputs from other brain areas

• One primary mechanism of hypothalamic interaction is through the pituitary gland

• The pituitary gland releases hormones, and has two main but separate parts:

  • Posterior pituitary

  • Anterior pituitary

• The way in which the hypothalamus interacts with these parts of the pituitary is different

Posterior Pituitary

• Secretes two principal hormones:

  • Oxytocin

  • Vasopressin

• Neurons in the supraoptic nuclei and paraventricular nuclei of the hypothalamus synthesize these hormones

• The hormones travel along the pituitary stalk and into the blood supply in the posterior pituitary

• Because there are released into the blood supply of the posterior pituitary, they are called “posterior pituitary hormones”

Anterior Pituitary

• The hypothalamus communicates with the anterior pituitary in a different way, requiring additional steps

• Some hypothalamic neuroendocrine cells synthesize releasing hormones

• Axons from these cells coverage on the median eminence, above the pituitary stalk

• Releasing hormones are secreted into blood vessels called the hypophyseal portal system, and are carried to the anterior pituitary

• The releasing hormones stimulate specific cells in anterior pituitary to release tropic hormones into general circulation, where they’ll travel through the body to their targets

• How will the hormone know where to have action?

  • It’s looking for the correct receptor

Hormones can affect both Physiology as well as Behavior

• Physiology: Oxytocin stimulates uterine contractions and is involved in milk letdown (nursing)

• Behavior: Oxytocin is released during nursing interactions and during orgasm to facilitate bonding; in female prairie voles, it promotes pair-bonds; Vasopressin facilitates the formation of pair-bonds in male prairie voles

Secretion of the Anterior Pituitary

Transient vs Permanent Effects of Hormones

Recall that steroid hormones bind to their receptors inside cells and can alter gene expression; this means they can increase or decrease production of various proteins and affect many cellular processes

• In adulthood, these effects are short-term, or transient

• This action early during development is permanent

Sex Determination

The process by which the decision is made for a fetus to develop as a male or a female

• Chromosome driven

• If the sperm that enters the egg has a Y chromosome, the offspring is male; if an X chromosome, the offspring is female

Sex Differentiation

The process by which individuals develop either male or female bodies and behaviors

• Hormone driven

Levels of Sex Determination/Differentiation

Gonads

When the gonads are first made, they are bipotential → meaning the same gonad can become either testes or ovaries

• The Y chromosome has a gene (the SRY gene, or sex-determining region of the Y chromosome) that codes for the development of testes from the bipotential gonad

• Without an SRY gene, an ovary forms

Hormones Secreted Early on by Gonads, Mainly from the Testes, Direct Sexual Differentiation of Internal Sex Organs

In Males, the Wolffian Ducts

• The precursor to the male system; develop into the epididymis, vas deferens, and seminal vesicles, and the Mullerian system shrinks

In Females, the Mullerian Ducts

• The precursor to the female system; develop into the oviducts, uterus, and vagine, the Wolffian system degenerates

If Testes are Present…

• Anti-Mullerian Hormone (AMH) causes regression of the Mullerian system

• Testosterone masculinizes the internal organ by promoting development of the Wolffian system

• Testosterone can be converted to dihydrotestosterone (DHT), an androgen, via the enzyme 5α- reductase, which masculinizes external structures

• Testosterone can also be aromatized to estradiol, an estrogen, via aromatase, which masculaines the brain

Development of Human External Genitalia

• This system is also first bipotential

• The hormones change the tissues into male-like or female-like

  • The presence of DHT masculinizes the structures

  • The lack of DHT feminizes them

Flowchart of Sexual Differentiation and Gender Identity

Turner’s Syndrome

(Chromosomal Condition)

A person only has one sex chromosome; a single X

• The individual develops as a female due to lack of the SRY gene, with abnormal ovaries (no steroid hormone production or eggs)

• Estrogen treatment induces breast growth and a female- typical puberty

Klinefelter’s Syndrome

(Chromosomal Condition)

A person has an extra chromosome, XXY

• A masculine body develops because of the Y chromosome

• Testes and penis are abnormally small

• Low testosterone production; little to no sperm are produced

• In this case, hormone replacement therapy is also. required for development of secondary sex characteristics

Congenital Adrenal Hyperplasia (CAH)

• Starts with the hypothalamic-pituitary-adrenal axis (or, HPA axis)

• Patients with CAH lack the enzyme (21-hydroxylase) that produces cortisol, so there is no negative feedback (from adrenal gland back to hypothalamus)

• This results in a much higher amount of hormone production, and the adrenal gland becomes enlarged

• The precursor that makes cortisol (17-hydroxyprogesterone, or 17-OHP) builds up, and the adrenal gland can turn the 17-OHP into other androgens like testosterone

• External genitalia in females is partially masculinized because of the exposure to increased DHT during development

  • Recall, DHT comes from Testosterone

• Exogenous cortisol is given after birth to halt excess androgen production

• Can occur in XX or XY

Prader Scale for Scoring Degrees of Genital Virilization

A clinical rating system used to measure the degree of external genital virilization, most commonly in 46,XX infants with CAH

• Stage 0: Normal female genitalia

• Stage I: Slightly enlarged clitoris, but everything else looks completely typical for a female.

• Stage II: Enlarged clitoris and the lower part of the outer lips (labia) are fused together. The openings begin to join closer together.

• Stage III: Notably larger clitoris that looks like a small penis. The outer lips are almost completely fused, leaving just one single opening for both urine and the vagina

• Stage IV: Looks mostly male. There is a penis-like structure and an empty scrotum (fused outer lips). The opening for urine is located at the base of the penis rather than the tip.

• Stage V: Looks completely male, but the scrotum is empty because there are no testicles inside.

• Stage VI: Normal male genitalia

Stages III through V are frequently classified clinically as ambiguous genitalia

In conditions like 21-hydroxylase deficiency CAH, higher Prader scores generally correlate with lower residual enzyme activity and higher fetal androgen exposure.

Androgen Insensitivity Syndrome (AIS)

Occurs in XY People with Defective Androgen Receptors (So, Androgens Cannot have Action)

• They will develop testes because of the SRY gene on the Y chromosome

• They will produce male-typical hormones such as Testosterone, DHT, AMH, and Estrogen

  • AMH acts perfectly during fetal development and wipes out the internal female structures

  • Because estrogen receptors work perfectly, this hormone acts completely

  • Testosterone and therefore DHT don’t work

• These individuals have female phenotype

Masculinization/Feminization of Brain

• Estradiol (converted from testosterone by aromatase) masculinizes the brain during early development

• Occurs (primarily) in males, since ovaries don’t produce hormones until puberty

Sexual Dimorphism (In Brain)

• Sexual dimporshim refers to the condition in which males and females exhibit marked sex differences in appearance

• When we talk about sex differences in the brain, it may be in number or density of neurons, dendritic branching, or connectivity

Sexually Dimorphic Nucleus of the POA (SDN-POA)

• In rats, a nucleus in the preoptic area called the sexually dimorphic nucleus of the POA (SDN-POA) is larger in males than in females

  • The area is important for reproductive behaviors in males

• When a female is injected with testosterone at the time of the male perinatal surge, she develops a large SDN-POA (masculinized brain)

• When a female receives an injection at later times, such as puberty, the testosterone has no effect on the size of a female’s SDN-POA; only transient effects

Organizational vs. Activational Effect of Hormones

• The organizational effect of estradiol permanently alters the brain by doing things like altering apoptosis (cell death), changing synaptic connectivity, and affecting densities

  • The organization effect occurs early in development during the critical period, when the brain is still developing

• This is in contrast to a temporary activational effect of hormones (like when we talk about hormones acting in adulthood)

Organizational:

• Structural changes in brain

• Permanent

• Occurs before brain matures

• Critical period

Activational:

• Biochemical changes

• Transitory

• Occurs in adulthood

• No sensitive period

Can the Same Hormone be Both Organizational AND Activational?

Yes! The deciding factor for what kind of effect the hormone will have is the timing of its action

• Steroid hormones have an organizational effect only when present during the critical period of development

• Depending on the species and the behavior, this period may be before birth or just afterwards, in the neonatal period

“Male” and “Female” Hormones

NO STEROID IS FOUND EXCLUSIVELY IN EITHER MALES OR FEMALES; RATHER, THE TWO SEXES DIFFER IN THE PROPORTION OF THESE STEROIDS

Why aren’t Female Brains Masculinized during Fetal Development, even though Females have Estrogens?

1.) Alpha-fetoprotein blocks maternal and placental estrogens from entering the fetal brain

2.) Fetal ovaries remain inactive, until puberty, and do not produce the high surge of hormones required to trigger masculinization

What are the Two Purposes of the Gonads?

1.) Production of gametes (sperm in males; eggs in females)

2.) Production of steroid hormones

• Required for: development of the body and the brain, production of gametes, encouraging behaviors that bring gametes together

Male Vs. Female Gonads

Male Gonads = testes; primary steroid produced is testosterone, which is an androgen

Female Gonads = ovaries; primary steroids produced are estrogens (estradiol) and progestins (progesterone)

What Does it Take for Reproduction to be Successful?

1.) Gamete Production and Release

2.) Bringing Gametes Together (Reproduction)

What controls these?

• Hormones!

• Importantly, the hormones that lead to development of the gametes are the same ones that allow for the behavior to occur

Gonadal Steroids

Gonadal Steroids Activate Reproductive Behavior

-circulating gonadal steroid hormones act upon the neural circuitry already in place in the brain, and are required for males and females of many species to engage in sexual activity

-gonadectomy (removing gonads) eliminates sexual interest and behavior (like in Berthold’s experiment)

Hormonal Control of Reproduction in Females

-In rats, females ovulate, or release eggs, every 4-5 days

-This is called the estrous cycle

• very similar to menstrual cycle in humans

-This is controlled by hormones via the hypothalamic-pituitary gonadal (HPG) axis

-Hormones associated with maternal instincts (like lactation) suppress reproductive desires

Hormonal Control of Reproduction in Females: Female HPG Axis

-The hypothalamus kicks everything off by releasing gonadotropin releasing-hormone (GnRH) in a pulsatile fashion

-GnRH stimulates the anterior pituitary to release follicle stimulating hormone (FSH) and luteinizing hormone (LH)

-FSH acts on the ovary to cause development of the follicle (egg); LH increases release of estradiol from the ovary

-Estradiol acts to increase further LH secretion (positive feedback), resulting in a surge of LH that causes ovulation

-Progesterone (P) production then increases, inhibiting the hypothalamus from releasing more GnRH (negative feedback)

-If the egg isn’t fertilized, P drops and the cycle starts over again

• If the egg isn’t fertilized, P drops and the cycle starts over again

• If its fertilized, P stays high to put a hold on the cycle

Hormonal Control of Reproduction in Females: Female Behavioral Receptivity

-The rise in estradiol followed by progesterone during the ovulatory cycle are also integral for female sexual behavior, increasing her receptivity and motivation for sex during behavioral estrus (or heat)

• A female who’s in estrus will exhibit lordosis when a male mounts her, allowing for copulation to occur

• A female who is not in estrus will fight a male who makes advances

Female Hormonal Contraceptive

-Oral contraceptives contain synthetic progesterone that inhibits release of GnRH

• The lack of GnRH prevents release of FSH and LH, so no egg is released by the ovary

• Sometimes estrogens are added to the Pill for physiological benefit, but progesterone is the active ingredient

Hormonal Control of Reproduction in Males

-Males also have an HPG axis

-The hypothalamic cells that release GnRH do so in a steady fashion, not in pulses, like in females

-This results in the testes producing testosterone (T) in the Leydig cells and sperm in the Sertoli cells

-Because the male axis is less pulsatile, production of T and sperm remain fairly consistent once they begin at puberty (unlike the cyclical nature of the female cycle)

Hormonal Control of Reproduction in Males: Sexual Behavior

-Testosterone is important!

• A castrated male loses interest in mating because testosterone is no longer produced

• Behavior is restored with testosterone treatment

-The level of testosterone doesn’t seem to matter, in that having higher levels doesn’t further increase sexual behavior (both in humans as well as many animals; except in seasonal breeders like male red deer!)

The Neural Circuitry of the Brain Regulates Reproductive Behavior

-In female rats, the ventromedial hypothalamus (VMH) is crucial to the lordosis response through steroid actions

1.) Centrally (in brain and spinal cord) estrogen acts to increase dendritic branching and connections of neurons in the VMH and periaqueductal gray (PAG)

2.) Periphery, estrogen increases sensitivity of sensory fields in the rump

3.) Estrogen also stimulates production of progesterone receptors, which is important for behavior receptivity and motivation

-The VMH sends exons to the periaqueductal gray in the midbrain, which projects to the medullary reticular formation in the hindbrain

-This in turn projects to the spinal cord via the reticulospinal tract

-As the male mounts, sensory information that comes in via the spinal cords combines with information from the brain, and the female exhibits lordosis

• Note that there’s no “decision” to exhibit lordosis; it is a simple reflex that doesn’t reach the brain

-In male rats, the medial preoptic area (mPOA) coordinates male copulatory behavior

-The mPOA sends axons to the ventral midbrain then to the basal ganglia to coordinate mounting

-Axons also project through brainstem nuclei to the spinal cord

Pheromones Guide Reproductive Behavior in Many Species

-Pheromones are chemical signals that communicate information between animals of the same species to help coordinate their reproductive activities

-The vomeronasal organ (VNO) consists of specialized receptor cells near to but separate from the olfactory epithelium and detects pheromones, which activaye male arousal

-VNO information is sent to the accessory olfactory bulb, which then projects to the medial amygdala, and in turn to the mPOA

-Altogether, then MPOA seems to integrate hormonal and sensory info, such as pheromones, and coordinate the motor patterns of copulation

Humans are Different when it comes to Sexual Behavior!

-Humans and other primates are capable of engaging in sexual activity at any point in theri cycles

-But, there have been some reported effects of hormones on sexual motivation

• Some studies show a peak in sexual motivation around the time of ovulation

• A low dose of testosterone can stimulate interest and activity in men that do not produce androgens due to lack of GnRH neurons in the hypothalamus

• Testosterone appears to increase sexual motivation in women, too

Optogenetics

-Hegemann and Nagel observed light-sensitive algae (Chlamydomonas)

• Channelrhodopsin: Light-sensitive, non-specific cation channel (+ in)

• Blue Light: Activation of Cells

-Deisseroth introduced channelrhodopsin to neurons in a dish

-Deisseroth introduced channelrhodopsin to mice in vivo

• Was applied to rodents to activate neurons during behavior

-Opsins: Light-gated ion channels that differ in types of ions, and light color that activates the channel

• allowing the passage of different ions allows activation and inactivation of neurons

Patient H.M

-Patient H.M (Henry Molaison) suffered from severe epilepsy

-After many things didn’t work, a decision was made to remove the brain regions doctors thought were giving him issues

-While his seizures went away, he had new problems: his memory was shot

Retrograde vs. Anterograde Amnesia

-Retrograde Amnesia: loss of memories formed prior to onset of amnesia

-Anterograde Amnesia: the inability to form new memories after onset of disorder

Two Main Kinds of Memory

-Declarative Memory: facts and information acquired through learning that can be stated or described; used to answer “what” questions

-Nondeclarative (Procedural) Memory: shown by performance rather than recollection; used to answer “how” questions

H.M & Mirror Tracing Task

H.M. was able to improve his motor skills with practice, but he could not remember having done the task previously

-H.M was unable to form new declarative memories but he was capable of procedural memory exemplified by the skill of mirror tracing

H.M Brain Regions

*The Hippocampal Formation: composed of the hippocampus, parahippocampal gyrus, subiculum, and entorhinal cortex, all of which play significant roles in memory formation

1.) Without a hippocampus, H.M. was unable to form new declarative memories

• The hippocampus is critical for declarative memory formation

2.) H.M. was able to form new procedural (non declarative) memories

• These are supported by distinct brain structures: the basal ganglia and cerebellum

3.) H.M. retained memories from early childhood

• The hippocampus cannot be the long-term storage site of memories

Patient K.C.

-Patient K.C was in a motorcycle accident when he was 30 and sustained significant damage to his frontal and parietal cortex, and sever shrinkage of the hippocampus and parahippocampal cortex

-K.C. couldn’t retrieve personal declarative (episodic) memory

• But, he still retained generalized declarative memory

-This also showed that the cortex is essential for long-term storage of memories once they are formed

Subtypes of Declarative Memory & Non Declarative Memory

Declarative Memory:

• Semantic Memory: Generalized Memory

• Episodic Memory: Detailed Autobiographical Memory

Non Declarative Memory

• Skill Learning: Learning to perform a task requiring motor coordination (mirror tracing)

• Priming: Repetition priming, a change in stimulus processing due to prior exposure to the stimulus

• Associative Learning: The association of two stimuli or of a stimulus and a response

Associative Learning

-Learning about relationships, or the process by which an association between two stimuli is established

• Also referred to as conditioning

• An unconditioned response becomes associated with a condition stimulus

• This is

Classical Conditioning

• An unconditioned response becomes associated with a conditioned stimulus

• This is learned through repeated pairings of the conditioned stimulus with an unconditioned stimulus to produce a conditioned response

• Pavlov’s test!

Operant Conditioning

An association is made between a behavior (action) and a consequence (reward or punishment)

3 General Stages of Long Term Memory

-Encoding: When sensory information is brought in to short-term/working memory

-Consolidation: Transferring information from short to long-term memory/storage

-Retrieval: Taking information out of long-term storage

Neuroplasticity

The ability of neurons and neural circuits to be remodeled in response to experience or the environment

-The synaptic plasticity hypothesis: synapses between neurons can be created and modified by experience

Memory Storage Requires Physical Changes in the Brain

-Changes can be measured physiologically, and may be presynaptic, postsynaptic, or both

-Changes include:

• Increased neurotransmitter release, and/or

• Changes in neurotransmitter-receptor interaction

-These increase the response in the postsynaptic cell

-Some changes may result in structural changes at the synapse

• New synapses could form with training/use, or some could be eliminated with lack of use

• Training might also lead to synaptic reorganization

Hebbian Synapses and LTP can Account for Changes in Synapse Strength

-In 1949, Donald Hebb proposed the idea that: CELLS THAT FIRE TOGETHER WIRE TOGETHER

• This means that if a presynaptic neuron repeatedly activates a postsynaptic neuron, the synaptic connection between them will become stronger and more stable

-These groups of neurons (cell assemblies) could then act together to store memories

-Long-term potentiation (LTP) is a stable and enduring increase in the effectiveness of synapses which causes the addition of AMPA receptors on the postsynaptic membrane

-Weakening of synaptic efficiency (long-term depression; LTD) can also encode information

Hallucinogen (aka Psychedelics)

Alter sensory perception and can produce peculiar experiences

-Have diverse neural actions, including those on the noradrenergic, serotonergic, ACh, and opiate systems

• LSD (acid), mescaline (peyote), and psilocybin (magic mushrooms) have predominantly visual effects through serotonin receptors

• Psilocybin can reduce activity in the medial prefrontal cortex and anterior cingulate cortex, brain regions that inhibit limbic emotion and processing

Two Major Categories of Psychedelics

1.) Classical (or Serotonergic) Psychedelics

• act predominantly upon 5-HT2 receptors

• ex: LSD (acid); DMT; psilocybin (“shrooms”); mescaline

2.) Non-Classical Psychedelics

• other hallucinogens that cause visual

What is being on Psychedelics like?

-Common Experiences:

• Heightened emotional sensitivity and creativity

• Euphoria or paranoia (good trip vs. bad trip)

• Loss of balance and fatigue

• Increased introspection

• Inability to sleep and loss of appetite

• Hallucination

  • More commonly manifest as visual distortions more so than seeing entities that don’t exist

Psychedelics aren’t a Recent Pharmacological Invention

-While psychedelics are gaining popularity for its medicinal properties in our society, they have been used worldwide for millennia in many indigenous communities for medicine and ritual practices

• Peyote: Central/Northern Mexico

• Ayahuasca: Northern South America (present day Ecuador, Peru, Colombia)

• Iboga: West Central Africa (present day Gabon, DPRC, and Cameroon)

How do Psychedelics Work?

-Classical psychedelics work through its agonism of 5-HT receptors (most notably 5-HT2A and 2-HT2C)

• This action suppresses the intrinsic excitability of pyramidal neurons the prefrontal cortex (ex; action upon 5-HT receptors on dendrites make cells less likely to fire) BUT these drugs also facilitate glutamate release when the neurons do fire

  • A possible explanation for the effects of a trip, but no concrete answers yet

-A single dose of a psychedelic also enhances synaptogenesis

Current Medicinal Applications of Psychedelics in the US

-Depression

• 1-2 doses of psilocybin may even outperform SSRI’s as shown in a clinical trial comparing psilocybin to escitalopram (Lexapro)

-Post-Traumatic Stress Disorder (PTSD)

• psychedelics may be used in combination with psychotherapy to reprocess traumatic events

-Substance Use Disorder: alcoholism, smoking cessation, and possible application in opiate dependence

• an interesting case report of a woman who took 500x the recreational dose of LSD: she was able to wean herself off morphine with minimal withdrawal symptoms for her chronic pain

-In healthy individuals: may also enhance long-term cognitive function

• One study demonstrated increased cognitive flexibility 3 weeks after a single dose in mice

If Psychedelics have a Bunch of Benefits, why aren’t we using them to Treat Psychiatric Disorders all the Time?

1.) Legal Issues: The controlled substances act of 1970 signed placed enormous restrictions upon the use and distribution of psychedelics

-Most psychedelics are listed under “Schedule I”: the most restricted drug schedule

• Criteria:

  • The drug has a high potential for abuse

  • The drugs has no currently accepted medical use in treated in the US

  • There is a lack of accepted safety for use of the drug or substance under medical supervision

2.) Negative Side Effects of Psychedelics:

• Hallucinogen Persisting Perception Disorder: disorder in which there are lingering visual distortions following psychedelic use

  • Varies in degree of severity, but most commonly appears in the form of visual snow, auras, and halos around objects

  • Colloquially called a “perma-trip”, although this disorder is rarely permanent

Can you Overdose on Psychedelics?

-There have been no reported cases of fatal overdose of LSD or psilocybin

• 0.2% of mushroom users have reported needing emergency medical attention after usage, the lowest rate of any illicit druga

• a set of case reports found that LSD overdoses rarely result in substantial long-term negative health consequences

• THIS ISN’T THE CASE FOR NON-CLASSICAL PSYCHEDELICS

  • non classical psychedelics are odd and can be very dangerous in large amounts due to their actions on life-sustaining processes

Why is it so Hard to OD on Classical Psychedelics?

-Classical psychedelics have low toxicity due to a favorable receptor profile

• i.e. they don’t act as strongly upon receptors involved in life-sustaining processes than the ones that produce the psychoactive effects

-Large doses also result in highly overwhelming subjective experiences, which can be good, but can also be a traumatic experience

-A single use of psychedelics downregulates 5-HT2 receptors, building functional tolerance

Zygote

A fertilized egg (egg + sperm)

A Human Embryo Develops 3 Cell Layers

-This is happens as the result of the process of gastrulation:

• ectoderm, mesoderm, endoderm

-Ectoderm, the outer layer, becomes the nervous system

Stages of Neuronal Development

-As the ectoderm thickens, it grows in a flat neural plate

-Uneven rates of cell division form the neural groove, which will become the midline

-The cells continue to push upwards and the neural groove becomes the neural tube, which will become the central nervous system

-The neural crest cells pinch off at the top and will migrate extensively to contribute to the peripheral nervous system

-The anterior part of the neural tube has three subdivisions, the forebrain, the midbrain, and the hindbrain

-The interior of the neural tube become the cerebral ventricles

-After 10 weeks, the embryo is called a fetus

Neural Development is Guided by the Interactions of Genetic and Environmental Factors

-Genotype: the sum of all the genetic information that we inherit is called genotype

• determined upon fertilization and doesn’t change

-Phenotype: the sum of the physical characteristics that make up an individual

• phenotype does change since its affected by experience

• this is how genetically identical twins can look different

-whether and when cells actually use genes during neural development is controlled by environmental influences, including experiences

-we say that a cell expresses a gene when it transcribes the gene and starts making the protein it encodes; this is called gene expression

-gene expression helps guide cellular differentiation, which is when cells become a particular type (like a neuron) depending on what genes are expresses

-gene expression can also result in long-term behavioral changes in the organism due to early experiences

Epigenetics

The study of factors that affect gene expression without changing the sequence of the genes

-Different ways to alter gene expression include histone modification and methylation

-Methylation modifies the DNA and reduces expression of the genes following the site of methylation

-Various experiences affect methylation, including early life experiences

• In rodents, maternal care programs offspring behavior responses

• Low licking and grooming results in increased methylation of the stress hormone receptor gene, so less of the receptors are made

  • Less stress hormone receptors means more stress hormone needs to be produced before the stress axis can be shut off (negative feedback shuts off system!)

  • So animals exhibit a heightened stress axis and higher anxiety

• High licking & grooming results in reduced methylation of the stress hormone receptor gene, so MORE of the receptors are made

  • More stress hormone receptors means you can shut the stress axis off sooner, as the hormone can find a receptor more rapidly

  • The animal exhibit a reduced stress response and lower anxiety

-Whether it’s better to have a heightened stress response, or a more responsive one that shuts off sooner depends on the animals situation!

Intrinsic Factors

Many cells are influenced by intrinsic factors, or instructions from within the cell

-Ex; Nematode: C. elegans

• this worm has a transparent body, making it easy to study

• each cell can be mapped and is born with specific instructions as to its fate; this is called lineage

  • lineage is the only factor that dictates to a cell what its fate will be in C. elegans

Extrinsic Factors

In other species, cells are influenced by intrinsic and extrinsic factors, or things in the environment

• these things include other cells (cell-to-cell interactions), or chemicals in their environment that can turn on or off certain genes

  • this allows for more flexibility as there are extra cells around to fill in if they are needed

• some extrinsic factors negatively impact development, like teratogens or alcohol

  • teratology: the study of pathological effects of early exposure to toxic substances

• intellectual disability refers to a variety of conditions that impede mental growth

  • a transient lack of oxygen at birth, known as hypoxia, can affect the brain

  • undernourished mothers may have underweight children who may suffer from brain abnormalities

  • maternal viral infections and drug exposure can cause developmental disorders

Phenylketonuria (PKU)

-A recessive genetic disorder where the individual doesn’t produce an enzyme that metabolizes phenylalanine, an amino acid present in a variety of foods

-as a result, the brain can be damaged because phenylalanine builds up, which becomes toxic

-this is detected shortly after birth, and the child is placed on a low-phenylalanine diet to reduce brain impairment (especially important before the age of 2)

Intrinsic and Extrinsic Factors that Affect Neural Development

Development of the Nervous System can be Divided into Six Distinct Stages

1.) Neurogenesis: mitotic production of neurons from nonneuronal cells

2.) Cell Migration: movement of cells to establish distinct populations

3.) Differentiation: transformation of precursor cells into distinctive neurons or glial cells

4.) Synaptogenesis: establishment of synaptic connections

5.) Cell Death

6.) Synapse Rearrangement: loss or development of synapses, to refine synaptic connections