Final

Neuromodulators secreted from a neuron can function at

- the postsynaptic neurons

- the neuron itself

- neurons and glia cells in the surrounding region

Neurons can communicate with each other through

- chemical and electrical synapses

- wiring transmission and volume transmission

- gap junctions

Which following molecule is not one of the four major neuromodulators in human brain?

glutamate

Which physiological activity shows circadian rhythms normally?

- body temperature

- plasma cortisol level

- melatonin level

T/F: Circadian rhythm requires a functional retinal for visual inputs

false

Which of the following is the function of limbic system?

- motivation

- emotion

- learning and memory

Which of the following is part of the limbic system?

hippocampus, amygdala, hypothalamus

Which of the following is a circadian gene

PER, CRY, BMAL

Which of the following is a sleep stage right before wake up

REM

Which of the following is affected by sleep deprivation and night-shift work?

- Reduced sperm count and increased number of deformed sperm

- Decreased libido

- Decreased bone density

- Increased rate of miscarriage in the first trimester

Which of the following brain region is most widely recognized for emotion control?

Amygdala

Which of the following subnucleus is considered as output center of amygdala?

Central nucleus of amygdala (CeA)

The freezing behavior during fear response is controlled by which of the following brain region?

Central gray (CG) or periaqueductal gray (PAG)

Which of the following is a component of the homeostasis model?

- input

- output

- set point

- feed back

Which of the following play a role for homeostasis feedback to regulate stress response?

Cortisol

Gut communicates with brain through which of the following pathway?

Immune system, vagus nerve, endocrine system

What is the function of gut bacteria?

- Regulate energy metabolism

- Affect mood and cognition

- Help digestion

Which of the following CAN NOT circulate between two parabiosis linked animals?

Leptin receptor

Neurons in which of the following brain region have been demonstrated to regulate appetite?

- Arcuate nucleus

- Paraventricular hypothalamus

- Brain stem parabrachial nucleus

What are diffuse modulatory systems? List the four major systems (provide diagrams) and compare their source location, their projections and their common features.

Diffuse modulatory systems utilize neuromodulators for volume transmission that diffuse throughout the brain that modulate the threshold of inhibition/excitation.

Norepinephrine

1. Source location - locus coeruleus

2. Projections to hypothalamus and amygdala, cerebellum, thalamus, BF, olfactory cortex, hippocampus, olfactory bulb, neocortex

3. Functions to in general increase brain response

Serotonin

1. Source location - raphe nuclei

2. Projections to LC, cerebellum, SNc/VTA, hypothalamus and amygdala, thalamus, BF, striatum, hippocampus, olfactory cortex, olfactory bulb, neocortex

3. Important in control of mood and emotions

Dopamine

1. Source location - VTA and substantia nigra

2. Projections to amygdala, ventral striatum, olfactory cortex, dorsal striatum, prefrontal cortex

3. Functions in voluntary movement and reward system

Acetylcholine

1. Source locations - septal nuclei, nucleus basils, pontomesencephalotegmental complex

2. Projections to amygdala, hippocampus, olfactory bulb, neocortex

3. Functions is not completely known but is involved in sleep cycle and learning and memory

What behaviors are typically associated with activation of each of the 4 major neuromodulatory systems?

Norepinephrine

- Regulation of arousal, sleep, attention, learning and memory, mood, and brain metabolism

- Increase brain responsiveness, info processing

Serotonin

- Fire during wakefulness

Involved in sleep/wake

- Part of reticular activating system

- Control mood and emotional behaviors

Dopamine

- VTA: reward system that reinforces adaptive behaviors

- Substantia nigra: control voluntary movements; degeneration correlates with Parkinson's disease

Acetylcholine

- Not completely known

Plays role in arousal, sleep-wake cycles, learning and memory

Why might there be multiple side effects related to use of drugs that affect the neuromodulatory systems themselves or their receptors?

Side effects are common because neuromodulators and their receptors are diffuse throughout the brain, many drugs have "off-target" effects. Same receptors can be in different brain regions that mediate different behaviors. Certain medications/drugs may act on more than one neuromodulatory system receptors, leading to side effects.

How is a circadian rhythm generated and how are the circuits entrained by light in the SCN? Be able to outline the pathways involved and explain the role of rods and cones vs ipRGCs. What experiments can show ipRGCs involvement?

Circadian rhythm is generated/controlled via the suprachiasmatic nucleus (SCN), an important nucleus in the hypothalamus. The SCN is affected by light due to having connections from retinal ganglion cells (RGCs) via the retino-hypothalamic tract. The cells that are capable of providing information for the circadian rhythm are intrinsically photo-sensitive retinal ganglion cells (ipRGCs). ipRGCs respond to light directly and therefore, even if rods and cones are ablated, circadian rhythm can stay intact.

The SCN controls circadian fluctuations in body temperature via its connections to particular centers in the hypothalamus. Would you expect the SCN neurons to be sensitive to body temperature? Give your reasoning.

Yes, likely at least some are thermosensitive in their firing rate in order to have controlled regulation of body temperature pathway.

Why would providing only dim lights in the workplace for night-shift workers make it hard for them to adjust to this schedule? Explain the underlying physiology (think about ipRGC and SCN responses to dim light).

ipRGCs in the SCN neurons firing rate is increased in response to light followed by the SCN sending signals to signify it is daytime

with dim lighting it can trick the brain into thinking it is time to be awake

another factor is melatonin is also secreted based on light intensity which when manipulated can help to trick the brain into thinking it is daytime

Describe some possible consequences of poor adaptation to night-shift work. Why would this happen? Consider not only light, but also food intake and physical activity and their role in entrainment of circadian rhythms in your answer.

Male:

i. Decreased muscle mass and strength

ii. Decreased bone density

iii. Reduction in sperm count and increased amount of deformed sperm

iv. Decreased libido

Female

i. Decreased follicle-releasing hormone

ii. Changes to menstrual cycle

iii. Decreased libido

iv. Increased rate of miscarriage in the first trimester

This is due to the body not following the correct circadian rhythm and not being able to conserve energy, cellular restoration affected, memory, learning, etc.

Since the SCN is responsible for regulating the autonomous nervous system, endocrine system and the immune system, poor adaptation to night-shift could cause disturbances in their eating, sleeping and social schedules.

Many companies that have employees working in shifts around the clock assign workers to different shifts (day, evening, night) in the duration of a week; others use a block scheduling pattern (on nights for a month, on days or evenings for 2 months). If you were a consultant giving recommendations for improving worker performance, which would you recommend? Provide the physiological rationale for your recommendation.

Most likely the 1- and 2-month pattern over a week so that your circadian rhythm has time to adjust. For example, this would give time for melatonin release to resync up with when you must go to sleep; changing every week would likely not allow for your body to get all the positive effects of sleep.

Electroencephalography (EEG) has been used to characterize different patterns of sleep. Stage 1 and 2 of sleep is characterized by high frequency activity. What causes the EEG signal?

Thalamic neurons have low-threshold calcium channels. During human sleep, thalamic afferent stimulation is low and membrane potential is low, causing calcium channel opening, a large amount of calcium ion influx, forming a short excitatory postsynaptic potential (EPSP)

Describe the architecture of a night's sleep. Include stages, cycle length, duration, change in proportion of REM and non-REM sleep over the night, and typical EEG patterns for each stage.

Non-Rem1: Theta waves

Non-Rem 2: sleep spindles, k complexes

Non-Rem 3: delta waves

Rem: fast random

Melatonin is available over the counter and often is used to induce sleep, especially when there is a jet lag situation. Explain the physiological reasoning behind this. Include the endogenous source of melatonin in the brain as well as the SCN-pineal circuit interactions.

Taking melatonin exogenously, usually through a pill or tablet, can help reset your circadian rhythm. This is helpful especially in cases of jet lag. This is because your rhythm needs to be retrained due to the extreme shift in time and light/dark exposure. Taking melatonin will decrease SCN firing and suppress activity. Normally, light signals are required to begin the melatonin production processes. The anterior hypothalamus and SCN become activated, when excite the super cervical ganglion to the pineal gland. The melatonin is then secreted and feeds back to the SCN to inhibit activation. Oral melatonin skips the process and can go right to decreasing the activity of the SCN, leading to the sleep phase of circadian rhythm.

What is emotion? What are the characteristics that distinguish emotion from reflex?

Emotions are biological states associated with the nervous system brought on by neurophysiological changes variously associated with thoughts, feelings, behavioral responses, and a degree of pleasure or displeasure

Emotions are classified according to their valence and intensity and have a contextual element unlike reflexes

What are the main brain structures in the limbic circuitry? What are the main behaviors/functions associated with these brain structures?

Hypothalamus - monitoring bodily functions and states

Amygdala - emotions and responses to emotions

Hippocampus - learning and memory

What is fear conditioning, explain the concepts of CS and US.

Fear conditioning is an experiment done in which to correlation a stimulus with a fear response

CS stands for conditioned stimulus and US stands for unconditioned stimulus

i. Conditioned stimulus is a stimulus that is attempted to correlate with a fear response in fear conditioning

ii. Unconditioned stimulus is a natural response

What are the classical neural circuits that control conditioned fear response? Describe the major neural pathways for sensory inputs, how the information is processed and control the motor outputs.

Innate threat --> sensory system (auditory and visual --> IA --> ABA) + (olfactory --> MA) --> VMH --> PAG --> freezing and/or flight

Learned threat --> sensory systems --> IA --> BA + itc --> CeA --> PAG --> freezing and/or flight

Describe the difference between innate vs. learned fear, and fear vs. anxiety?

Innate fear is an ingrained fear of something within a person while a learned fear is a developed fear of something

Fear is a reaction to a specific, observable danger while anxiety is a sustained mental health disorder that can be triggered by stress and can be internal or external

i. Fear is usually a shorter period of time compared to anxiety

Describe the major sensory inputs of stress, the brain regions process stress information, and how the brain systems regulate the stress response.

Major sensory inputs of stress are internal neuromodulatory system such as sickness or inflammation and external sensory inputs

The brain regions that process stress information are the limbic system (limbic forebrain, BST, hypothalamus, brainstem, CVO)

The brain regulates a stress response through the use of the HPA system in order to control stress hormones

Describe the HPA system. Note the hormones released at each level and their functions.

Stressor --> hypothalamus + PVN --(CRH)--> anterior pituitary --(ACTH)--> adrenal cortex --(CORT)--> negative feedback --> hypothalamus + anterior pituitary

What is the homeostasis model? Please use it to explain HPA stress response.

Homeostasis model is used to regulate response of stress

Input (interoceptive, sensory) + biological set point -> hypothalamic nuclei --> output (autonomic, endocrine, behavioral) --(feedback)--> input

How does chronic stress affect the HPA Axis?

Chronic stress increases levels of CRF, ACTH, and corticosterone which affect the levels of hormones in the HPA system

What do we mean by the term "gut-brain axis?"

It's the connection between the central and enteric nervous system

It's the mediation of the effects of the gut microbiota

Describe the typical microbiota of the gut. What is its source at birth, how does it change with age, and how does it change with diet?

At birth as passage through the vaginal canal and contact with the mother's skin the infant is exposed to microorganisms

This can change with age as we are exposed to different environments

This can change with diet as we try different foods

What are the functions of the gut microbiota? Describe the bidirectional interactions between the gut and the CNS.

Gut bacteria can help modulate gut movement and leakiness, metabolism (of fats and plant-based starches), affects absorption, production of vitamins, stimulation of BDNF production, neutralizing drugs, modification of immune response, regulation of host energy metabolism

Brain --> gut --> brain --> etc.

i. Vagus nerve plays a large role

Describe the experiments in mice receiving fecal transplants from obese and thin twins that showed the contribution of gut microbiota to body metabolism.

In the experiments with mice receiving fecal transplants there was shown a change in fat mass for both over the course of the experiment

What is the proposed role for microbiota of the gut in brain development?

It is proposed to have a role in memory and learning, sleep, social behavior, etc.

What are the two types of transmission discussed in neuromodulation?

Wiring transmission and volume transmission.

What is the primary role of neuromodulators in the nervous system?

They modulate the level or threshold of excitation/inhibition and have many other functions.

What are the four major diffuse neuromodulatory systems in humans?

Norepinephrine, Serotonin, Dopamine, and Acetylcholine.

What is the difference in timing response between wiring transmission and volume transmission?

Wiring transmission is fast (a few ms), while volume transmission is slow (seconds to hours or longer).

What is the defining feature of the Noradrenergic Locus Coeruleus?

It makes diffuse connections and regulates attention, arousal, sleep-wake cycles, and more.

Which nuclei innervate the brain and modulate pain-related sensation?

The rostral serotonergic raphe nuclei innervate the brain, while the caudal nuclei innervate the spinal cord.

What neurotransmitter is primarily involved in the reward system and reinforcement of adaptive behaviors?

Dopamine, released from the VTA (ventral tegmental area).

What are some effects of atypical antipsychotics?

Weight gain, sedation, seizures, agranulocytosis, and some risk of tardive dyskinesia.

How does wiring transmission differ in terms of target specificity compared to volume transmission?

Wiring transmission is point-to-point, targeting a limited number of cells, while volume transmission can affect a diverse range of target cells.

What physiological processes are associated with cholinergic systems in the brain?

Arousal, sleep-wake cycles, learning, and memory.

What is wiring transmission?

A fast, point-to-point communication using neurotransmitters across synapses or gap junctions.

What is volume transmission?

A slower, diffuse signaling using neuromodulators that travel through extracellular fluid, CSF, or blood.

How does a neuromodulator work?

By altering the excitability or responsiveness of neurons through second-messenger pathways, often with widespread and long-lasting effects.

What are the key differences between wiring and volume transmission?

Wiring: fast, local, neurotransmitters, synaptic. Volume: slow, diffuse, neuromodulators, extracellular or CSF/blood.

Name four mechanisms of volume transmission.

Simple diffusion, CSF-mediated vector diffusion, nerve bundle-associated, perivascular space-associated.

Can a molecule be both a neurotransmitter and a neuromodulator?

Yes, depending on the context and mechanism of release.

What do neuromodulators do in a CPG circuit?

They modulate the output pattern without altering the wiring

What are the common features of diffuse neuromodulatory systems?

Small nuclei origin, widespread projections, influence thousands of neurons, use second messengers, and change brain area modes.

Where is the noradrenergic system based?

Locus Coeruleus.

Functions of the noradrenergic system?

Attention, arousal, sleep-wake cycles, memory, anxiety, pain, and brain metabolism.

Where is the serotonergic system located?

Raphe nuclei: rostral for brain, caudal for spinal cord

Functions of the serotonergic system?

Mood, emotion, sleep-wake regulation, and pain modulation

Where is the dopaminergic system based?

Substantia nigra and ventral tegmental area.

Functions of the dopaminergic system?

Voluntary movement, reward, reinforcement, Parkinson’s disease link.

Where is the cholinergic system based?

Basal forebrain and brainstem complexes.

Functions of the cholinergic system?

Arousal, sleep, learning, memory; first affected in Alzheimer’s

What do conventional antipsychotics block?

D2 dopamine receptors, histamine H1, α1-adrenergic, muscarinic cholinergic receptors.

Side effects of conventional antipsychotics?

Varied by drug, but include sedation, movement disorders, etc.

What are atypical antipsychotics?

Drugs like Clozaril and Zyprexa with broader receptor profiles.

Clozaril side effects?

Weight gain, sedation, seizures, agranulocytosis, some tardive dyskinesia risk.

Where is 5HT1A receptor found?

Medial PFC, entorhinal cortex, cingulate cortex, hippocampus, septum, amygdala, olfactory system.

Where is 5HT1B/1D receptor found?

Basal ganglia, nucleus accumbens, cortex layer 5, cerebellum Purkinje cells.

Where is 5HT2A receptor found?

Neocortex, hippocampus CA3, striatum.

Where is 5HT2C receptor found?

PFC, nucleus accumbens, hippocampus, amygdala, caudate, substantia nigra.

Where is 5HT3 receptor found?

Neocortex, olfactory cortex, hippocampus, amygdala.

Where is 5HT4 receptor found?

Olfactory tubercle, caudate-putamen, ventral striatum, hippocampus.

Where is 5HT5A receptor found?

Hippocampus, habenula, raphe nuclei.

Where is 5HT6 receptor found?

Ventral striatum, nucleus accumbens, caudate, PFC, hypothalamus, hippocampus

Where is 5HT7 receptor found?

Thalamus, hippocampus, septum, hypothalamus, amygdala, raphe.

What receptors do conventional antipsychotics (e.g., D2 antagonists) block?

D2 dopamine receptors, histamine H1 receptors, α1-adrenergic receptors, and muscarinic cholinergic receptors.

What is the mechanism of action for conventional antipsychotics?

They block D2 dopamine receptors and other receptors like H1, α1-adrenergic, and muscarinic cholinergic receptors.

What drugs are examples of atypical antipsychotics?

Clozaril and Zyprexa.

Which receptors do atypical antipsychotics block that contribute to weight gain and sedation?

5HT2C and histamine H1 receptors.

What are the side effects of atypical antipsychotics?

Weight gain, sedation, seizures, agranulocytosis, and some risk of tardive dyskinesia.

What is the origin of the noradrenergic system in the brain?

The locus coeruleus.

What functions are regulated by the noradrenergic system?

Attention, arousal, sleep-wake cycles, learning, mood, and pain.

How does the noradrenergic system affect brain responsiveness?

It increases brain responsiveness and speeds up information processing.

Where is the serotonergic system located?

In the raphe nuclei — rostral part projects to the brain, caudal part to the spinal cord.

What functions does the serotonergic system regulate?

Sleep-wake cycles, mood, and emotional behaviors.

When do serotonergic neurons fire most?

During wakefulness.

Where are 5HT1A serotonin receptors found?

Medial prefrontal cortex (mPFC), hippocampus, and amygdala.

Where are 5HT2A serotonin receptors found?

Neocortex, hippocampal CA3 region, and striatum.

Where are 5HT2C serotonin receptors found?

Prefrontal cortex (PFC), nucleus accumbens, and limbic regions.

Where are 5HT7 serotonin receptors found?

Thalamus, hippocampus, raphe nuclei, and hypothalamus.

Where does the dopaminergic system originate?

Substantia nigra (SN) and ventral tegmental area (VTA).

What is the function of the SN-to-striatum dopaminergic projection?

Controls voluntary movement; degeneration causes Parkinson’s disease.