NROS418 Exam 3

CSF circulation is greatest during sleep, esp SWS. Why? What is CSF anyway and where is it produced?

CSF, or cerebrospinal fluid, is a colorless fluid which can be found surrounding the central nervous system structures. During SWS, blood flows out of the brain and CSF flows into the brain, a process thought to be responsible for clearing toxins that accumulate over the course of the day. This speculation comes from the decrease of CSF flow during sleep seen in the elderly and those with alzheimers.

State the effects of the parasympathetic and sympathetic divisions on the following organs: heart, blood vessels, gastrointestinal tract, lungs, adrenal medulla, and external genitalia, cardiac muscles.

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

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What are the targets of the ventro-lateral pre-optic area neurons?

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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.

Are sensitive to body temp for two reasons. One they are sensitive because they are zeitgebers so fluctuations help time the body. Example melatonin peak secretions actually times the lowest point of body temp and then two hours later the temp is lower. If something is off SCn wil correct Criteria for being circadian can persist within homeostatic bounds, uses narrow range of temp and will adjust itself and not break down or phase shift unless a drastic shift it will be sensitive and it will phase shift accordingly

How do these features change over a lifetime? Compare infancy, adolescence and aging.

As you get older, you sleep less and the cycle lengths begin to shorten. As an infant is when you have the most sleep which is about 16-18 hours and their rhythm is not fully established. As an adolescence you begin to sleep a little less and there is a shift in their melatonin production. Not to mention they also have many psychological factors to account for. Lastly, at an older age they still need the usual 8 hours of sleep but they either wake up more often during the night or have more trouble falling asleep. Cycles become abnormal

Why are circadian rhythms important for animal adaptation to the environment. Include both daily and seasonal considerations.

Circadian rhythms are important for behaviors to take place at the most opportunistic times of day

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

Developing embryos are exposed to bacteria in utero. While infants born vaginally receive a seed of their microbiota during passage through the birth canal via exposure to maternal vaginal and perhaps fecal microbes, infants born by cesarean delivery receive their first major exposure to bacteria from their mother's skin and the hospital environment.,Bifidobacterium, Lactobacillus, Enterobacteriaceae, and Staphylococcus are the most populous organisms in the GI of the healthy, vaginally delivered infant GI tract, followed by Veillonella and Lachnospiraceae. The composition of the infant's gut microbiota is unstable until approximately 2 years of age, ie, until the child begins to eat solid food. Breastfed infants have a different microbiome than formula-fed infants, and by age of 3 years, the microbiota of most infants stabilizes and develops toward what becomes the adult microbial composition. In healthy adults, the gut microbiota is dominated by only a few phyla, as noted above, and is characterized by a wide diversity of bacterial species. The human microbiome changes with age, normally becoming less diverse in the elderly as a result of higher numbers of Bacteroides species and reduced numbers of Clostridium groups. Even if the microbiome of adults is relatively stable when compared with that of infants or elderly, several factors can dramatically influence its composition over a relatively short period of time. Such factors include antibiotic treatment, stress, infection, host genetics, and die. The study of germ-free animals shows that brain development is abnormal when the gut microbiome is missing. The gut microbiome influences the inflammatory reactions within the brain by modulating the activation of microglial cells and affecting myelination36 and neurogenesis in adult brains. Fecal transplantation between mouse strains with different levels of anxiety has demonstrated that the microbiota can even change behavioral characteristics of mammals by altering brain chemistry.

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

Diffuse modulatory systems are where there are multiple axonal projections and diffuse into other cells. The four major pathways and their common features are, simple diffusion (autocrine and paracrine), vector (endocrine like), Nerve bundle association, and perivascular space association which are both diffusion pathways. LOCATION?(first lecture)

Human breast milk contains elements that are not used by human infants and fiber has long been known to be important to gut health. Why would each of these elements be important?

It feeds the good bacteria and starves the bad bacteria.

What is the location and function of hypocretin neurons?

Hypocretin, also known as Orexin, is a neuropeptide that regulates arousal, wakefulness, and appetite. Orexinergic neurons in the lateral hypothalamic group are closely associated with reward related functions, such as conditioned place preference. These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex. In contrast to the lateral hypothalamic neurons, the perifornical-dorsal group of orexinergic neurons involved in functions related to arousal and autonomic response. These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes

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

Hypothalamus (Monitoring bodily functions and states (fight or flight/rest and digest), Thalamus, Amygdala (Emotions, and Response to those emotions) and Hippocampus (Learning and Memory) picture

What are the effects of the sympathetic and parasympathetic nervous system on gut motility, secretions and blood flow?

In general, sympathetic stimulation causes inhibition of gastrointestinal secretion and motor activity, and contraction of gastrointestinal sphincters and blood vessels. Conversely, parasympathetic stimuli typically stimulate these digestive activities.

Melatonin is available over the counter and often is used to induce sleep, esp 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.

Melatonin is a zeitgeber so by taking melatonin you are shifting when it is available in the body and being secreted. This affects where the peak of secretion is as well effectively shifting the rhythm and allowing easier entrainment.

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

Mice receiving the fecal matter from the obese twin gained more weight than control, mice with fecal matter from thin twin gained less weight than control. Everything else was held constant meaning that the gut microbiome can affect the metabolism of food and nutrient storage and use in the body.

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 were done to show ipRGC involvement?

Molecular clock generates the rhythms (need to know how) and light entrains the rhythms by slowing or speeding up the clock (also need to know how) see circadian II

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

Neuromodulators are extremely diverse in their target cells, target specificity, and most importantly in their function. Because these molecules serve a wide variety of roles, altering them through drugs is likely to cause multiple unintended effects.

Comment on the abundance of neurotransmitters in the gut and indicate those that are especially abundant.

Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin (5HT) are the main neurotransmitters secreted and located in the gut. The gut contains a high concentration of these neurotransmitters and dysregulation of their levels have been linked to diseases such as Parkinson's and Alzheimer's as well as psychological diseases such as depression and anxiety. The gut functions almost like a second brain with an abundance of other neurotransmitters such as melatonin, nitrous oxide, and GABA as well as many others are located in the gut. Many enzymes are also needed to break down food and NT when the get into the gut and dysregulation of these enzymes or the absence of them can also result in disease or disease phenotypes.

What are the organ targets of each division? Do all organs receive both SNS and PSNS input?

Not all organs receive both SNS and PSNS input. The adrenal glands, Liver, and Sweat Glands all receive input from the SNS but not the PSNS. Many peripheral targets of both SNS and PSNS inputs have opposing behaviors depending on the input (Eyes dilate with SNS input and constrict with PSNS input) picture

Why does the daily activity rhythm shift in the absence of light? What other signals might the brain use in entraining sleep/wake cycles?

Our sleep/wake cycle is slightly longer than 24 hours, causing our daily activity rhythm to shift in the absence of light. Noises may also signal the brain during entrainment of sleep/wake cycles. Other beings in the natural environment have responses to light changes that can be audible such as birds chirping.

Describe the major differences between the parasympathetic and sympathetic subsystems of the autonomic nervous system (ANS) in terms of function, structure, and neurotransmitters.

PSNS Function: Control resting bodily function SNS Function: Control bodily response when threatened or "fight or flight" PSNS Structure/NT: Longer post-ganglionic, Ach is main NT, muscarinic (M2 and M3) and nicotinic receptors. SNS Structure/NT: Shorter post-ganglionic; NE and Ach are main NT, Alpha1/2 and Beta1/2 receptors.

List the major divisions of the gut. What is the length of the gut from esophagus to anus?

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What is an axonal varicosity - provide a diagram. Compare point-to-point and diffuse modulatory transmission.

Point to point is when the action potentials are released across the synapse and bind to the postsynaptic receptors that are temporally and spatially accurate whereas diffuse modulatory transmission has divergent axonal projections that communicate with other neurons.

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.

Poor adaptation to night-shift work has been associated with a wide range of consequences to one's health. This includes altered reaction to anesthesia, and higher incidence of parkinsons and alzheimers. For synchronous biological activity, all activities would need to take place at night as opposed to during the day like eating, working, and socializing. For night shift workers, they likely experience discrepancies over the course of the day and over the course of a week (thinking about days off of work) which desynchronize their biological rhythms, wreaking havoc on their health.

Describe the hypothalamic-pituitary portal circulation. Note the hormones released at each level.

Portal circulation first starts in a capillary bed. Capillaries will begin to extend away the bed and merge to form a set of veins that then divide to form a second capillary bed. So the blood collected from the first capillary bed is solely directed to the tissues nourished by the second capillary bed. The hypothalamic-pituitary portal system has the first capillary bed in the hypothalamus and sends it through the plexus of veins surrounding the pituitary stalk. This blood then gets directed to the second capillary bed in the anterior pituitary gland. So, the neurohormones secreted by the neuroendocrine cells in the hypothalamus are directly to the cells of the anterior pituitary without ever entering the general circulatory system in the body.

Compare the axonal lengths of the sympathetic (SNS) and parasympathetic (PSNS) pre-ganglionic and post-ganglionic neurons. Indicate which are typically myelinated.

Pre-ganglionic axon length in the Sympathetic nervous system is shorter than the parasympathetic axonal length. The post-synaptic length and the opposite with sympathetic generally being longer than the parasympathetic. The Pre-ganglionic axons for both the para and sympathetic nervous systems are myelinated where the post-ganglionic axon is not for both. However there is some evidence and models that show the PSNS might have myelinated post-ganglionic axons

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).

SCN neurons increase their firing rate in response to light received at ipRGCs. The SCN then sends those signals to a variety of places which signal that it is day time/time to be awake and active. Dim light still produces an increase in the firing rate, which confuses the rhythm in which people sleep at night and are awake during the day. Also remember that Melatonin times night length and that it is secreted based on light intensity

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.

Sleep Stages: 1. Interim between consciousness and sleep -stage 2 after 5-15 min 2. Heart rate slows, brain does less complicated tasks -Another 15 mi, move in non-REM sleep, the delta stage 3. Body makes repairs 4. Body temperature and BP decrease -REM: increase in eye movement, heart rate, breathing, BP and temperature -NREM sleep: our brain uses its neurochemicals to inhibit the thalamus, this keeps the sensory stimuli from reaching the cortex. We need to prevent information from activating the cortex in order to fall asleep

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?

Source at birth is either through the birth canal from the mother or the air in the operating room with a C section. Over time diet and environment will add to the microbe or take away from it making it unique and diverse. picture

What are the major divisions of the autonomic nervous system?

Sympathetic, Parasympathetic and Enteric Nervous systems

Essentially all cells have the cellular clock pathways and within an organ, most of the cells are synchronized to each other by either diffusible signals or network interactions. Why would it be important to synchronize all the clocks in the body, which is the role of the SCN? Be as specific as possible and give examples. Hint: think food.

Synchronizing all clocks of the body is important in order to continue as a human being. There are things that must be done at certain times like cell regulation and hormone balances and if these types of clocks were not in sync it would throw the body off a routine and lead to side effects that could potentially be fatal.

Why might it be important to consider time of day in giving a drug? Consider timing of a cancer drug, for example.

Taking the drug at a given time during the day and at the same time during the day leads to the maximal results. There are also many side effects with different drugs that you would not want to endure during the day and are asked to take it at night. These times are also important in order to make sure there is some of the said drug in your system at all times so it does not become resistant to the virus being attacked.

In what way is the ENS, which is a division of the autonomic nervous system, unique from the PSNS and the SNS? Think about reflex arcs in your answer. Why is this important functionally?

The ENS has what are known as reflex arcs which are complete reflex circuits that detect the physiological condition of the gastrointestinal tract, integrate information about the state of the gastrointestinal tract, and provide outputs to control gut movement, fluid exchange between the gut and its lumen, and local blood flow (Gershon 2005; Furness 2006) and is capable of local autonomous function vs. the PSNS and SNS which cannot function independently from the brain. The ENS has extensive, two-way, connections with the central nervous system (CNS), and works in concert with the CNS to control the digestive system in the context of local and whole body physiological demands. http://www.scholarpedia.org/article/Enteric_nervous_system This is an excellent resource for the ENS.

Define the term "enteric nervous system." How many neurons are involved in the ENS?

The ENS is one of the main divisions of the autonomic nervous system (ANS). It governs the function of the gastrointestinal tract and is capable of acting independently of both the sympathetic and parasympathetic nervous systems, although it may be influenced by them (Vagas and prevertebral ganglia innervations); however, it does not need this innervation to function. The neurons in this system control secretion of gastrointestinal enzymes as well as the motor functions of the gut.

What transmitter is released from the SNS and PSNS pre and post-ganglionic neurons and which sub-types of transmitter receptors are present on the post-ganglionic neurons

The PSNS uses Acetylcholine as its primary neurotransmitter. It is released from the preganglionic terminal onto nicotinic receptors post-synaptically. The post-ganglionic neurons release Ach onto muscarinic receptors in the periphery (M2 and M3). M2 receptors- acted on by acetylcholine, M2 receptors are located in the heart; stimulation of these receptors causes the heart to slow (decreased heart rate and contractility and an increase in refractoriness). M3 receptors- located throughout the body; activation causes increased synthesis of nitric oxide, which results in relaxation of cardiac smooth muscle cells. Norepiniphrine is typically released by neurons in the SNS post-ganglionic and NE or Ach can be release pre-ganglionic. NE and Ach act on either Alpha 1/2 or Beta ½ adrenergic receptors. Alpha 1 receptors exert their effect on smooth muscle, mainly by constriction. Effects may include constriction of arteries and veins, decreased motility within the GI (gastrointestinal) tract, and constriction of the pupil. Alpa1 receptors are usually located postsynaptically. Alpha 2 receptors bind both epinephrine and norepinephrine, thus reducing the effect of alpha 1 receptors to a certain extent. However, alpha 2 receptors have several specific effects of their own, including vasoconstriction. Effects may include coronary artery constriction, constriction of smooth muscle, constriction of veins, decreased intestinal motility and inhibition of insulin release. Beta 1 receptors exert their effect mostly on the heart, causing an increase in cardiac output, increased contractility and increased cardiac conduction, leading to an increase in heart rate. There is also stimulation of the salivary glands. Beta 2 receptors exert their effect mostly on the skeletal and cardiac muscles. Increased contraction speed and mass of muscles, as well as dilation of blood vessels occurs. Receptors are stimulated by circulating neurotransmitters (catecholamines).

Explain what the C and S processes are and how they interact to produce the sleep-wake cycle.

The S process is reliant on sleep debt, or how much sleep one requires. This debt accumulates over the course of the day and is relieved by sleeping. Process C is the process of the body's circadian clocks which determine states of wakefulness and sleepiness. The two processes work together to determine when a person needs to go to sleep and how much sleep they will need to get.

What do we mean when we say the SCN has a core and shell region? List the major inputs and outputs of the core and shell regions.

The core of the SCN receives light input from the retina and sends out projections to the shell region. The shell sends output projections and diffuse signals into peripheral areas such as the fore brain, hypothalamus, and thalamic nuclei, pre-optic area, raphe nuclei, and locus coeruleus. You can differentiate the shell and core regions by the type of cells that are represented (VIP for the core and AVP for the shell). Picture

How does chronic stress affect the HPA Axis?

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What do we mean when we talk about the gut/brain axis?

The gut-brain axis is a bidirectional link between the central nervous system and the enteric nervous system. It allows for both direct and indirect communication between emotional and cognitive centers in the brain with peripheral intestinal functions. The GBA also involves the endocrine (hypothalamic-pituitary-adrenal axis), immune (cytokine and chemokines) and the autonomic nervous system (ANS). The GBA primarily combines the sympathetic and parasympathetic arms of the autonomic nervous system (ANS), which drives both afferent and efferent neural signals between the gut and the brain, respectively. https://psychscenehub.com/psychinsights/the-simplified-guide-to-the-gut-brain-axis/

How does the HPA Axis regulate stress homeostatically?

The hypothalamic-pituitary-adrenal (HPA) axis orchestrates the physiological response to unpredictable acute stressors and has prominent circadian activity. This circadian activity synchronizes peripheral circadian clocks to daily environmental cycles, thereby promoting homeostasis. Chronic stress results in a disruption of homeostatic glucocorticoid circadian rhythmicity which is correlated with an increased risk of developing pathological conditions including depression, diabetes and cancer. In order to restore homeostatic conditions, organisms activate a complex range of responses involving the endocrine, nervous, and immune systems, collectively known as the stress response [2]. The stress response serves to prioritize survival over less essential physiological functions, including growth and reproduction. The hypothalamic-pituitary-adrenal (HPA) axis, comprised of the hypothalamus, pituitary gland, and adrenal glands, regulates the body's adaptive response to stress [1]. Activation of the HPA axis triggers neurons in the paraventricular nucleus (PVN) of the hypothalamus to release corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which stimulate the anterior pituitary gland to produce and secrete adrenocorticotropic hormone (ACTH) [3]. In response, ACTH induces the synthesis and secretion of glucocorticoids (cortisol in humans and corticosterone in rodents), mineralocorticoids (aldosterone), and adrenal androgens, which are released from the adrenal cortex into the blood circulation [3,4]. Rising levels of cortisol inhibit further release of CRH and ACTH in a classic endocrine negative feedback loop, which enables the HPA axis to return to a physiological state following acute activation. As part of the physiological adaptation to stress, the HPA axis mediates the functions of the hypothalamic-adrenal-gonadal (HPG) axis, which is responsible for the maturation of the reproductive organs and the reproductive competence of an organism. The HPG axis controls the reproductive system through endocrine signaling, originating with hypothalamic secretion of gonadotropin-releasing hormone (GnRH). GnRH stimulates the gonadotroph cells of pituitary to synthesize and release follicle stimulating hormone (FSH) and luteinizing hormone (LH). In turn, FSH and LH act on the ovary to regulate oocyte maturation, ovulation, and steroid hormone production [5]. Activins, inhibins, and ovarian produced steroid hormones (estradiol and progesterone) feedback to regulate the secretion of the gonadotrophins [6]. Stress signaling impacts all levels of the HPG axis [7]. For example, high levels of glucocorticoids have inhibitory effects on the GnRH neurons, the pituitary gonadotrophs, and the gonads [7,8]. The purpose of this review is to briefly introduce the signaling mechanisms of stress hormones, summarize recent advances in our understanding of the effects of stress on fertility, and discuss current evidence that describes the long-term effects of stress experienced during in utero development.

Where do the cholinergic neuromodulator system, serotonin and norepinephrine neuromodulator systems arise from?

The neurotransmitter Norepinephrine is released by the Locus Coeruleus The neurotransmitter Serotonin is released from the Raphe Nuclei Picture

Several neuromodulatory systems are involved in initiating/maintaining an awake state. Draw one of these systems on a sagittal (side) view of the brain at the midline. If you gave a drug that partially blocked the receptors for these neuromodulators, what might the effect be on the sleep-wake cycle? Explain the underlying physiology.

The noradrenaline system is involved in sleep/wake cycles and other things. If a drug was given to partially block and make the system unable to work it would result in the person's inability to continue to stay awake and be in a constant state of fatigue. The physiology behind this is the fact that the locus coeruleus would be affected at most which is one of the main areas with arousal and attention. -similar to others like dopamine, check lecture

A common recommendation for improving sleep hygiene is eliminating all lights in the bedroom at night (including all those pesky LEDS that are on every piece of electronic anything that you own) and eliminating exposure to blue wavelengths (electronic screens esp) for a few hours before sleep. Explain the physiological basis for this recommendation.

This recommendation is so exogenous signals match those of the circadian rhythms and allow for a seamless transition into sleep. If there are still high levels of light in the environment, the SCN is still firing and signaling for wakefulness. If there are still high levels of light in the environment, melatonin isn't being released. These factors cause one to feel more awake and will cause difficulty in falling asleep. ipRGCs are most sensitive to blue light and blue light is the most prominent wavelength during the day

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

Typical behaviors involved with these systems have to do with the neurotransmitters that are targeted. For example, dopaminergic would result in behaviors of happiness whereas noradrenergic would result in behaviors like how easily you are aroused. Lecture for other 3

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.

Use of a block schedule