Wednesday, March 7, 2012

Brainstem and reward circuits in energy balance control

1Main Idea¶

Hedonic system includes parabrachial nucleus (PBN) and nucleus of the solitary tract (NST). The former is responsible for rescue of weight loss in ArGP ablated mice and the later has to do with reward pathway.

2GABA agonist and brainstem¶

• as mentioned in the first lecture, weight loss in ArGP ablated mice can be rescued by administrating GABA.
• only NPY neurons are previously characterized nucleus that is involved in energy regulation and releases GABA.
  • when the entire nucleus is taken out, weight loss and starvation, which is rescued by putting in GABA in the brain.
  • when knockout leptin, only mild obesity
  • so leptin is acting somewhere else on neurons that release GABA
• to examine specific site, GABA agonist (bretazenil) is put in the fourth ventricle and third ventricle
  • due to the flow of CSF, injection into the fourth ventricle would stay in that ventricle.
  • fourth ventricle is surrounded by brainstem.
  • third ventricle is surrounded by hypthalamus
  • is it hypothalamus or brainstem that is responsible for feeding rescue?
    • result: it's the brainstem (delivery of GABA agonist into the fourth ventricle restores body weght more efficiently than delivery inot the third ventricle) response is also dose-dependent.
  • since GABA is inhibitory, bretazenil injection results in reduced Fos activation in both parabrachial nucleus (PBN) and nucleus of the solitary tract (NST)
    • Fox is a marker fo neuronal activity
• results show that stimulating GABAergic signaling in PBN result in protectino against starvation in AgRP-ablated mice.

3Signals of satiation¶

• Satiation signals include:
  • mechanical distension in the stomach
  • nutrient stimulation of the intestine
  • intestinal hormones released
  • circulating nutrients
• satiation signals travel via vagal afferent neurons, which terminate on neurons of the NTS in brainstem.
  • NTS then project to many other neurons including those in the hypothalamus.
• so meal size is controlled by correlates of store energy (i.e. adiposity signals, like leptin and insulin)

4Leptin receptor¶

• expressed everywhere, many places in hypothaalmus.
  • densest expression in arcuate nucleus, where leptin, sinsulin, ghrelin, and nutrient signal.
• staining of phosphorylated STAT3 shows that lepin does act in arcuate nucleus and many other places.
• NTS also expresses leptin receptors.

5NTS¶

• gastric distension increases Fos immunoreactivity in NTS
  • gastric distension decrease food intake
• some leptin responsive cells also respond to gastric distension
  • gastric distension increases p-STAT3 staining.
• pSTAT3 and Fos stainings overlap. So some leptin responsvie cells respond to gastric distension.
• NPY versus leptin:
  • Given a degree of gastric distension :
  • NPY decreases firing of NPY neurons
  • leptin increaes firing of NPY neurons
• it's also shown that leptin delivered to the brainstem is sufficient to potentiate intake-suppressive effects of an otherwise ineffective voluem of gastric distension :
  • leptin sensitize NTS responses to gastric loads

6PBN¶

• nucleus of the pons
• GABAergic projections frmo AgRP and NPY neurons to PBN is necessary to maintain feeding behavior.

7Hedonic system¶

• mesolimbic doapmine system - reward pathway
• addicting drugs and food increase dopaminergic transmission from VTA onto other neurons such as nucleus accumbens
• reward pathway include:
  • VTA (ventral tegmental area)
  • laterla hypothalamus
  • arcuate nucleus
  • nucleus accumbens
  • all those express leptin receptor
• direct injectino of leptin into the VTA results in a reduction of food intake in rats. and it's dose-dependent.
• direct injection of ghrelin into the VTA does the opposite (increases food intake)
• GREASY FOOD TASTE GOOD: VTA-specifc knockdown fo leptin receptors result in increased sensitvity to highly palatable (fatty food or sugered food).
  • same thing occurs in trpm5-KO mice (mice without sweet receptors on their taste cells)
    • so brain can sense calories difference
  • the same effect is not seen when sucralos (anartificial sweetener, non-caloric) is used instead of sucrose.
• leptin also decreases neuronal activation by palatable food images.