Module 6 - Neural Control of Homeostasis

Question 1

L6.1 - Define and describe biological homeostasis

Answer 1

Homeostasis: the maintenance of the body’s internal environment within a narrow physiological range. It’s mediated by the hypothalamus signaling to the autonomic and endocrine systems.
homeostasis is present for water/salt content, blood sugar/pressure, sleep, temperature, fat storage, co2 levels in the blood.

Question 2

L6.1 - Define the different hypothalamic nuclei involved in homeostasis

Answer 2

For fat storage:
Arcuate nucleus as the main one, which projects to the paraventricular nucleus and the lateral hypothalamic area. It releases NPY to increase appetite and POMC to decrease it. Leptin modulates it signaling (the more leptin, the less eating)
The lateral hypothalamic area:
When excited: increased appetite, when inhibited: decreased appetite
the paraventricular nucleus
Activated when leptin is present (to decrease appetite)  when excited: releases ACRH and thyrotropin and activates the ANS
The ventromedial nucleus is important in appetite (feeling full – stopping eating).

Ghrelin can increase the appetite in the fasted state (opposite of leptin)
The hypothalamus

Question 3

L6.1 - Explain the physiological role of the hypothalamus

Answer 3

The hypothalamus is the organ that allows homeostasis of the body, which enables survival. It signals to the pituitary to release hormones in the bloodstream (endocrine signaling to modulate homeostasis) and modulates the autonomic nervous system. For the endocrine system, there is a feedback mechanism that will stop the signaling, which will enable the homeostasis.
It supports the regulation of: body temperature, appetite, sleep and stress/emotions.

Question 4

L6.1 - Describe basic methods to study homeostatic processes

Answer 4

For feeding:
Metabolic tools, looking at transgenic mice where certain factors are not present (Siamese twins’ experiments – wt and diabetic mice are stitched together to understand how the hormones affect each animal)
Behavioral experiments (push lever for sugar reward to understand motivation)
Food intake (food insecurities where the animals don’t know when we get food)
Single cell sequencing to understand the cell types in the hypothalamus.

Question 5

L6.2 - Describe anatomy, function and interplay between the hypothalamus and the pituitary

Answer 5

The hypothalamus compares the inputs from the brain and the body to the biological set point and modulates hereafter to ensure homeostasis is being kept.
The function is the modulation of homeostasis. Each hormone has a different function. E.g. for the HPA axis the CRH gets released from the periventricular neurons to the anterior pituitary, which projects ACTH to the adrenal gland, which releases cortisol to the body, where there is a negative feedback mechanism.
Different hypothalamus neurons project to different parts of the pituitary through different pathways.
The magnocellular neurons in the hypothalamus have a direct neuronal connection (neurohypofyse) to the posterior pituitary and therefore doesn’t have to release hormones to signal to the pituitary  release oxytocin and vasopressin.
The Parvicellular neurons in the hypothalamus projects to the anterior pituitary through the median eminence to the anterior pituitary. Hormones secreted include the Adrenocorticotropic Hormone (ACTH), thyroid stimulating hormone (TSH), Luteinizing and Follicle Stimulating Hormones (LH/FSH), Growth hormone and prolactin (PRL)

Question 6

L6.2 - Describe CNS-controlled hormonal regulation

Answer 6

The hypothalamus projects to the pituitary, which sends out hormone releasing factors to the PNS – the hormones can re-inter the brain through leaky areas of the BBB. These hormones extend past those of the glands and include endorphins, growth hormone, oxcytocin and prolactin
Hormones can be secreted based on the CNS responses  amygdala trigger HPA axis

Question 7

L6.2 - Explain brain-hypothalamus-pituitary-glandular regulation of homeostatic functions

Answer 7

Two examples were given:
The HPA (hypothalamus (CRH)  pituitary (ACTH)  Adrenal gland (cortisol)
This axis can be triggered by stressors and decreased when the hyp/puturitary sense at there is too much cortisol in the system. 
Cortisol can increase blood glucose, have anti-inflammatory effects and augments catecholamine response
The HPT axis (hypothalamus (TRH - thyroid releasing hormone)  pituitary (TSH)  Thyroid (T3 + T4)
T3 + T4 helps control metabolism and issues with the thyroid gives problems with temperature regulation
The HPG axis (hyp: GnRH  pur: LH/FSH  gonads: estrogen/progesterone and testosterone)

Question 8

L6.3 - Define the divisions of the autonomic nervous system

Answer 8

The parasymp (rest/digest), symp (fight/flight) and entric (gut) – you have preganglionic, postganglionic and effector cells.

Question 9

L6.3 - Describe the general functions of the autonomic nervous system

Answer 9

To modulate homeostasis. They’re both active at all times and “fight” for which one has the most power (it’s never just one or the other). They help to increase or decrease the blood pressure, breathing, urine and so forth.
The parasymp is “rest and digest”  slows heartbeat, increase digestion and constricts pupils
The symp is “fight and flight”  increases heart rate, decrease digestion and dilate pupils
The sympathetic system alone has control over sweat/adrenal glands and blood vessels

The enteric nervous system has the Myenteric (Auerbach’s) plexus and the Submucous (Meissner’s) plexus  can work independently, but is modulated by ANS inputs

Question 10

L6.3 - Describe and compare the anatomy of the sympathetic division with that of the parasympathetic division

Answer 10

Symapathetic: 1st neuron is in the imtermediate horn and 2nd in the sympathetic chain (T1-L2). Nicotine receptors for the 1st synapse (Ach) and alpha or beta receptors for the 2nd (NE)  long postganglionic fibers
Parasympathetic: 1st neuron in the sacral spinal cord or brain stem (intermediate spinal horn) and 2nd in ganglion close to the target organ.
Nicotine receptors for the 1st synapse (Ach) and muscarine for the 2nd (Ach)  short postganglionic fibers
The autonomic system is slower than the somatic one, as the ANS has 2 synapses and the 2nd uses metabotropic receptors

Question 11

L6.3 - Describe the fight-or-flight response

Answer 11

The amygdala Hyp  pituitary  adrenal medulla to release adrenaline based on visual input of threat (immediate response before conscious processing through the thalamus).
It’s mediated by the symp:
dilates pupils so more light comes in
Sweating
Breathing becomes more shallow, more O2 is taken up/more Co2 is released
HR increases, blood pressure increases with vasoconstriction
Blood goes from organs to muscles
Short terms: adrenaline (like an injection of stress) – long term: cortisol (like a drip)
 long term stress is a problem

Question 12

L6.4 - Define Interoception

Answer 12

To sense the internal start of the body
interoception is “inside sensing” - it’s information that can come from different organs and can be pain, organ sensation (heart beating), feeling hot/cold or similar feelings. Different hormones can signal about this and tell us when something is wrong (e.g. we’re hungry). It’s important to keep homeostasis by checking if the body needs anything or to monitor any changes in the bodily state. Intereceptive information is mediated by the NTS to the brain.

Question 13

L6.4 - Define and describe visceral nociceptors, baroreceptors and chemoreceptors

Answer 13

Visceral nociceptors mediate visceral pain and nociception (the physiological reaction to the tissue damage) - present in the heart, lung, bladder and gastrointestinal tract. Mainly mediated by c-fibers, making the signal slow and dull.
The adequate stimulus varies from area to area (they’re polymodal), but for the heart it could be H+ ions (seen in ischemia). In the lunges it will be irritant areoles and for the GI, irritation of the mucosa. It’s the stretch of the GI that is nociceptive and not a cut.
Having nociception in the heart might save your life when you have a heart attack

Baroreceptors are physiological receptors sense the change in stretch. They’re mainly talked about in the blood vessels (blood pressure), but are also found in lunges, the GI or bladder. They help us to maintain homeostasis. They can sense if we have too much or little pressure)

Chemoreceptors protect the body from toxins. They detect the change in PH, oxygen, CO2 tension and hydrogen ions. They are present in larger arteries or in the medulla and can regulate breathing.

Question 14

L6.4 - Describe the sensory component in autonomic regulation of cardiovascular function

Answer 14

All visceral receptors are necessary to mediate change in the input to the organs. Baroreceptors will detect pressure changes that it relies to regulatory areas, that will enable effector cells to change features of the organ to bring it back in homeostasis. Chemoreceptors mediate changes in respiration based on changes in PH, PO2 or PCO2 in the blood or in the medulla.
E.g. will baroreceptors detect too little stretch in the blood vessels, which will signal to cardiovascular centers and the sympathetic activation will be upregulated to increase the vasoconstriction and HR to increase the pressure.

Question 15

L6.5 - Define and describe a circadian rhythm

Answer 15

Life on earth is exposed to different light intensity – to adapt the circadian system is exposed to changes in light intensity. It was first investigated in plants.
Circadian rhythms are physical, mental, and behavioral changes that follow a 24-hour cycle.
It’s a 24-hour rhythm approximately. It has to be endogenous and self-sustained without external clue.
It modulates the level of certain ions (na+), catecholamines or temperatures based on time of day. Also affect when we’re tired. The circadian rhythm is displayed in a actogram.

Question 16

L6.5 - Describe the localization of the main circadian clock in the suprachiasmatic nucleus

Answer 16

The circadian rhythm is maintained by the suprachiasmatic nucleus (just above the optic chiasm in the anterior hypothalamus), which projects to the pineal gland, which produces melatonin to induce sleep.
If you lesion the suprachiasmatic nucleus, the circadian rhythm is thrown off. If you graft in a new one, you can gradually regain a rhythm (though this is the rhythm of the donor)
suprachiasmatic nucleus fires mainly during the daytime – inhibits the interneuron and at night we see disinhibition.

Question 17

L6.5 - Describe the overall anatomy of the circadian system

Answer 17

The input to the retina goes to the Suprachiasmatic nucleus, which projects (in a complicated way through interneurons) to the pineal gland. The Suprachiasmatic nucleus will inhibit the pineal gland during the day though signaling to the paraventricular nucleus (GABAergic) and stop firing at night for disinhibition.

Question 18

L6.5 - Explain the principle of the molecular circadian clock work, e.i. the role of clock genes

Answer 18

Just the principle, not the genes
The first clock gene (per) was found to have a rhythm of mRNA (higher transcription in the dark). Theory: the protein would have a feedback on the RNA or transcription
Per protein will form a dimer and inhibit its own expression –> oscillation in the system, giving the molecular clock. This process takes around 24 hours and enables the circadian rhythm. These genes are found mainly in the suprachiasmatic nucleus, but can also be present in the cerebral cortex or the cerebellum.

Take home: the clock genes are transcribed more during certain times of the day. Their resulting proteins will form dimers with other proteins to form feedback inhibition of the transcription.

Question 19

L6.5 - Describe the light input to the circadian system via photosensitive retinal ganglion cells

Answer 19

there is an input from the retina to the Suprachiasmatic nucleus. The clock of the Suprachiasmatic nucleus relies on the light levels, which is mediated by special photo receptors that are also ganglion cells (NOT rods and cones). The photoreceptors contain melanopsin (suppresses melatonin synthesis and is activated by light). Without this, the system is disturbed. If these are disturbed, the rods and cones can take over.
Light functions as an external cue for the circadian rhythm.

Question 20

L6.5 - Explain the regulation of circadian melatonin synthesis of the pineal gland

Answer 20

Pathway from the SC nucleus to the pineal gland
SC signals will signal to the pineal gland, where melatonin is synthesized from serotonin – the pineal gland on the back of the brain stem. The AANAT generates the rhythm for melatonin, as this is what synthesizes the NAS (intermediate step) to melatonin
Seretonine – AANAT  NAS – ASMT Melatonin.
neurons in the Suprachiasmatic nucleus has the clock genes, so their patterns will control the pineal gland and production of melatonin.

Question 21

L6.6 - Explain the two-process model of sleep regulation

Answer 21

2 main factors how tired you feel - these are the 2 processes
Process c: cardician machinery will anticipate changes in light. This is the awake drive.
Process s: length of wakefulness. This is the sleep drive/pressure (builds up during the day)

As sleepiness builds, you will fall asleep. The wakeful ness drive decreases as the night begins, so you can stay asleep. As there is no slippiness left, you wake up.
sleep homeostasis compensates for sleep loss (concerns duration and the “power” of it - more deep sleep lost the more it’s needed)

Question 22

L6.6 - Describe the neuroanatomical brain areas and pathways involved in sleep-wake regulation

Answer 22

Suprachiasmatic Nucleus is the central pacemaker of the brain – signals to the puturitaty (process c). problems: delayed sleep or fragmented or jet lag can affects process c
The activity of cholinergic neurons (release Ach) in the reticular activating system also seem to mediate wakefulness and REM sleep (their inactivity might mediate non-REM sleep)
The lateral hypothalamus and secrete Hcrt, which will trigger NE, serotonin and histamine containing areas to keep us awake. Hcrt stabilizes wakefulness (KO associated with Narcolapsy).
These circuits can be inhibited by the VLPO in the hypothalamus to induce sleep through GABA projections.
The thalamus drives the system when we’re asleep.

Then: the sleep pressure must be modulated by the brain through adenosine (ADP) - measured in HC - it increases as we get tired and decreases as we sleep. the receptor (A2A) is found in a sleep driving nucleus in the brain (preoptic nucleus) and, but the problem is that there is a large turnover
now we think phosphorylation of synaptic proteins might be important - proteins are phosphorylated when we’re awake and at some point, it’s saturated - this might trigger a sleep response and proteins would be de-phosphorylated while sleeping - sleep might be tracked on a synaptic level?

Question 23

L6.6 - To understand how external factors (including light, sound, temperature and stimulants) impact sleep

Answer 23

Caffeine makes it hard to fall asleep (Blocks adenosine receptors). Any external factor can wake you up, specifically if you’re in REM sleep. This is decided by the thalamus. Light will decrease chances of falling asleep through the photosensitive retinal ganglion cells signaling melanopsin from producing melatonin.
Immune activation in response to viral infection can also decrease sleep quality

Question 24

L6.6 - Describe different sleep stages, their characteristics and distribution during sleep

Answer 24

4 sleep stages: N1, N2, N3 and REM. Sleep becomes deeper and deeper until REM. REM looking in EEG like we’re awake. The muscle tone is low while in REM. When you close your eyes, you have N1  N2  N3. After a couple of hours, we go up to REM. If you wake up at night, it’s often during the REM phase. Sleep is often covered in the hypnogram.
You have sleep spindles (for memory consolidation) and k-complexes (shows if we’re being disturbed during sleep) in N2.
The earlier sleep stages are categorized by theta waves and deeper sleep by delta waves. REM sleep is associated with an awake-like EEG pattern (similar to beta waves)

Question 25

L6.6 - Explain the impact of sleep restriction/loss on brain function

Answer 25

Sleep deprivation leads to decreased performance due to failing concentration and your ability to judge your own performance drops as well. We observe a plateau in learning motor skills with disturbed sleep and a decrease in creativity with loss of REM sleep.
3 days of insufficient sleep make a significant difference from 6 to 8 hours. Memory formation might be impacted, and your brain won’t be “cleaned” as well by the glymphatic system (acumination of waste produces)
The postsynaptic density might shrink during sleep to promote learning when waking up.

Question 26

L6.1 - Explain the biological basis of the EEG signal

Answer 26

EEG is generated by the dipoles in neurons. The fact that the pyramidal neurons in the cortex are placed in parallel enables their dipoles to be stronger and send out a higher electrical signal. We measure post synaptic potential and not APs

Question 27

L6.1 - Describe different rhythms in the EEG signal as well as artefacts

Answer 27

Delta: deep sleep - 1-3 hz (look like mountains)
Theta: early sleep - 4-7 hz
Alpha: awake but relaxed - alpha 8-13 hz
Beta: awake and focused - 14-24 hz
Gamma - 25+ hz (squiculy lines)
You have sleep spindles (for memory consolidation) and k-complexes (shows if we’re being disturbed during sleep) in N2.

Question 28

L6.7 - Describe the biological regulation of body weight

Answer 28

It’s a balance between energy in and out (E_in – E_out = delta stored energy) – classic way of thinking. If you go a little over one day, it might even out another (homeostatic control). Problem: we don’t have the same metabolism or take up the same number of calories – 2-10% goes through without uptake. Another problem: it implies that you’re responsible for your weight – the body doesn’t correct everything. There is some decision making, but your homeostatic processes will influence you (you will be hungry when cutting calories).
40-60% is genetically determined - almost all genes associated with obesity was in the brain  points to obesity being a brain disease. There is a zone of indifference for homeostasis (around 10)  we might all have a different homeostatis setpoint?

Question 29

L6.7 - Describe the key signals that regulate food intake

Answer 29

Neuroendocrine signals can be sensed by the brain in the adipose (leptin) and sensed in the hypothalamus, where leptin inhibits ARPG and excites POMC. Some work on bone/muscle signaling or from signals in the liver. Signals from the gut can also decrease food-intake.

In the arcuate nucleus, AGRP/NYP code for hunger (when inhibited the PVN is disinhibited and we stop eating) and POMC neurons will signal for weightloss when activated.’
Leptin comes from adipose tissue and stops eating through AGRP and LHA inhibition and POMC excitation. POMC will excite the PVN to signal to the NTS, which decreases food intake.
Ghrelin come from the stomach and activates AGRP/NYP while inhibiting POMC to increase food intake. It also has effects on the reward system (VTA  Nucleus accumbence), which normally interacts with the LHA, what also signals for eating.

Question 30

L6.7 - Define the main brain regions involved in homeostatic and hedonic feeding

Answer 30

The arcuate nucleus (in the hypothalamus) signal to the lateral hypothalamus to start eating and paraventricular nucleus for stop (both when excited). Leptin has receptors in both (blocks one and promotes another).
Leptin is a long-term stop-eat signal.
VTA to NAc are connected to the lateral hyp (active when we eat) –> problem is that the endogenous hormones have to penetrate the BBB, so effectiveness is debated
POMC are activated by leptin and inhibit AGRP and increases NTS signaling to stop food intake. we don’t know how this works

Question 31

L6.7 - Describe pharmacological targeting of appetite to curb obesity

Answer 31

AGRP neurons would be great to target (inhibit) as they fire for hunger
The NMDA receptors are highly involved in obesity – we want to antagonize NMDA receptors (ketamine helps lose 3% body weight over time) – memantine (for AD – also an NMDA antagonist) helps a lot in weightless
By combining appetite lowering gut peptides (GLP1) with a small-molecule (NMDA antagonist) through a chemical linker  idea was to inhibit food want and need. The NMDA antagonist would target the NTS and the peptide the hypothalamus  very effective  lowers the insulin level

Question 32

L6.11 - Explain the role of the hypothalamo-gonadal endocrine axis, including its components and hormones

Answer 32

LH and FSH are release from the pituitary in response to the hypothalamic release of GnRH  triggers the gonads (ovaries or testes) to release either estrogen/progestogen or testosterone.
Both have a feedback mechanism to the hypothalamus, but the female system is more complex, as the presence of estrogen leads to more LH and FSH release to mediate ovulation during the menstrual cycle. Males work on a 24-hour sex-hormone cycle (peak in morning and decrease over the day), where the female one is 28 days (estrogen high around ovulation and progesterone increase between ovulation and menstruation).

Question 33

L6.11 - Describe theories behind puberty onset

Answer 33

What is puperty?: Primary changes = increase of hormones and secondary changes = physical changes
They might be linked, but not fully, as secondary changes are occurring a year earlier (perhaps due to obesity?). We see a correlation, but there is not a linear curve.

What triggers puberty:
We don’t really know.
Both weight increase and steroids can help trigger puberty onset, but neither are sufficient alone

The kisspeptin might be important in inducing puberty, specifically because it activates GnRH release. Neurons with it’s receptor (Kiss1) is found in the AV-PVN and arcuate nucleus and signal to the GnRH neurons for GnRH release. When knocking out kisspeptin, animals don’t sexually mature
It seems that while the receptor is always there, kisspeptin will increase during puperty to trigger activation
It seems that kisspeptin might be inhibited in the arcuate nucleus during childhood, but as puberty start, the Kiss1Rs become less sensitive to the inhibition and kisspeptin in the AV-PVN triggers GnRH release with the disinhibited arcuate nucleus.

Question 34

L6.11 - Define sexual dimorphism

Answer 34

Sexual dimorphism is the systematic difference in form between individuals of different sex in the same species

Question 35

L6.11 - Describe sexual dimorphism in the brain, including sex differences beyond reproduction

Answer 35

The SRY (sex reversal gene on the Y chromosome) gene on the Y chromosome allows men to develop differently from women. It’s not expressed in the brain.
In the motor cortex will have different projections in males/females to accommodate different genitalia
Females have far more neurons in the AV-PVn than males to control the menstrual cycle (there are higher kisspeptin levels) – their projections differ too. In contrast, male rats have a larger sexually dimorphic nucleus of the preoptic area (SDN-POA).

zebra finch brain - the male sings and the female can’t, as she doesn’t have the right neurons in the brain (missing area x)
the Tobaco hawk moth male has larger antenna, and the female has the ability to smell tobacco plant where she lays eggs. The male moth can sense smalls levels of female pheromones (males have macroglomerular complex in their brain)

Males have larger Sexual dimorphic nuclei in the POA (structural), but females have more kisspeptin neurons in this area Antero ventral preoptic area (AVPA) (functional)

Question 36

L6.11 - Explain the neurobiological mechanisms behind development of sexual dimorphism

Answer 36

The mechanisms behind the dimorphism seem to be mediated by both genetic and hormonal differences. The SKY gene enables a peak in testosterone during week 15 of development, which sex-sensitive neurons in the brain can convert into estradiol through the enzyme aromatase. Estradiol will agonize its receptors and cause downstream effects such as changes to neurotransmission and membrane permeability, but also modulation of transcription

Question 37

L6.10 - Explain the physiological mechanisms used by mammals to maintain body temperature homeostasis

Answer 37

Our core temperature will remain the same, but the shell (outer limbs) will vary.
We can increase heat by brown fat thermogenesis, muscle shivering, goose bumps and skin vasoconstriction (to keep the heat to the core).
We can cool down by sweating or by skin vasodilation. Most of these processes are mediated by the sympathetic system (Brown fat thermogenesis, vasoconstriction, sweating) and others the motor system (shivering)
Brown fat thermogenesis happens when norepinephrine binds to receptors on brown fat cells. Here it activates UCP1 in the mitochondria and increases the proton leak, leading to increased heat production and thermogenesis

Question 38

L6.10 - Describe the neurobiological processes that underlie peripheral temperature sensing, central signal integration, and activation of thermoregulatory responses by effector organs

Answer 38

Temperature homeostasis is regulated by the POA in the hypothalamus.
POA receives information from temperature sensitive fibers located in the skin, viscera,
spinal cord and brain (responsible for temperature sensing).
Here TRP-receptors are temperature gated ion channels and will open for different temperatures. TRP-A1 is for noxious cold, TRP-M8 is for cold (and mint), TRP-V3 or TRP-V4 is for sensing warmth and TRP-V1 and TRP-M3 for noxious heat (V1 also for capsaicin).
The TRP channels signal through the anterolateral tract, but can also trigger reflexes to e.g., withdraw hand from a hot plate.
POA sends signals for temperature adjustments to brown fat, muscle, blood vessels (effector organs).

TRP receptor continuum:
0 degrees: noxious cold max
10-20 degrees: noxious cold active
20-30 degrees: cold sensing max
40-43: warm sensing max
43: noxious warm activated
45-53: noxious warm peak