The Doperminergic System

Question 1

Three parts of the brain stem

Answer 1

1) mesencephalon/midbrain
- cerebral peduncles on ventral side with substantia nigra (part of basal ganglia)
- quadrigeminal plate with superior and inferior colliculi on dorsal side (backside)

2) pons (bridge)
- connected to cerebellum by thick fiber tracts (peduncles)
- at base of pons (ventral aspect) -> unpaired basilar artery (blood supply to vital brain stem structures)

3) medulla (oblongata)
- looks like thicker continuation of spinal cord
- contains vital centres for circulation and respiration
- decussation of pyramidal tract

Question 2

Cranial nerves

Answer 2

There are 12 on each side (24 in total)

• input from the head’s sensory systems and motor control of facial and laryngeal muscles
• brain stem lesion: can entail selective dysfunction of specific nerves while sparing others -> allows for clinical localisation

1) cranial nerves I: olfactory
- end in basal forebrain (above brain stem)
2) cranial nerves II: optic
- only sends collaterals to the brain stem (superior colliculi)
3) cranial nerves X: vagus nerve
4) cranial nerves XI: accessory
- ascend from spinal cord (fake cranial nerves)

Question 3

Emotion and Addiction

Answer 3

• emotional processing can Signal presence of (prospect for) reward or punishment and initiate motor programs to pursue or avoid
• dopamine codes for reward expectation
• most drugs of abuse (opioids, stimulants, alcohol, cannabinoids, etc) act on elements of the limbic circuitry
  -> unnaturally elevated neurotransmitter release with psychological alterations: dopamine from ventral tegmental area (VTA), noradrenaline, serotonin and others
  -> internalisation of receptors due to overstimulation
  -> dampened response of the emotional reinforcement circuitry to natural (less potent) awards

Question 4

Diversity of dopermingeric midbrain cells

Answer 4

• two distinct dopermingeric systems in the midbrain:
  1) substantia nigra pars compacta (SNc)
  2) ventral tegmental area (VTA)
• classifying doperminergic cells according to gene and protein expression shows a variety of subtypes
  -> some don’t strictly adhere to a SNc-VTA separation, show mixed properties or extend to surrounding nuclei

Question 5

Connectivity of VTA neurons

Answer 5

• VTA is origin of mesolimbic pathway (basal ganglia and amygdala) and mescocortical pathway (to preforntal cortex)
• main target site for VTA is ventral striatum (nucleus accumbens and ventral parts of putamen)
• VTA neurons activated by motivation and reward densly innervate the nucelus accumbens core region
  -> aversion-encoding neurons target nucleus accumbens shell region
• involved in incentive-based behaviour, motivation and cognition
• some VTA neurons co-transmit dopamine (= neuromodulator) with glutamate (=reward) or GABA (=aversion)

Question 6

Connectivity of SNc neurons

Answer 6

• ventral SNc is origin of nigrostriatal pathway
• ventral SNc neurons target dorsocaudal part of the striatum (caudate nucleus and dorsal putamen)
• phasic ventral SNc neuronal firing is associated with start-stop signals and accelaration in movement
  -> selective ablation of a ALDH141 subtype in rodents leads to a deficit in acquiring new motor skills while having no effect on consolidated skills

HOWEVER: dorsal and lateral neurons of SNc are more similar to VTA neurons, are implicated in salience and novelty detection, reward prediction and contribute to the mesolimbic pathway

Question 7

Selective vulnerability in Parkinson Disease (PD)

Answer 7

• ventral SNc cells contain less neuromelanin pigment than dorsal cells and are selectively lost in PD
• neuromelanin sequester toxic dopamine metabolites (quinones) and bind iron leading to less intracellular aggregation of α-synucelin (Lewi Bodies) and mitochondrial dysfunction (believed to be the cause of premature cell death)
  -> genetic variants may intensify vulnerability
• ventral SNc cells are much longer than VTA cells and have extremly branched axonal endings and show high intensity brust firing
• high baseline activity and little capacity to increase mitochondrial respiratory activity in case of stress
• multiple ‘hits’ make ventral SNc cells more vulnerable than other dopermingeric cells

Question 8

Physiology of sugar metabolism

Answer 8

• sugar = commonly sucrose (disaccharide) consisting of one glucose and one fructose molecule
• intramolecular bond is cleared in gut and glucose and fructose are absorbed via different metabolic pathways
• sugar generally signals high caloric value and the physiological responses are generally much stronger to glucose than to fructose
  -> glucose is the only nutrient that the brain can use for energy production
• high reward value of glucose for experimental animals (and humans)
  -> sugar-conditioning possible even without tasting the sweetness (eg direct intestinal infusion via gastric tube)
  -> cells necessary and sufficient for sugar conditioning are found in the proximal small intestine (duodenum, jejunum)

Question 9

Neuropod cells and the Vagus nerve

Answer 9

Discovery of a new cell type with neuron-like behaviour in the mucosal lining of the gut = neuropod cells
-> on binding of sodium-glucose co-transporter channels (SGLT1) influx of sodium
-> T1R3 taste-receptors (like receptors in mouth) start second-messenger cascade with release of Ca2+ from intracellular storages which opens a second set of Na+ TRPM5 channels
-> K-ATP-channels close on intracellular binding of ATP-increase (after intracellular glucose metabolisation)
-> voltage-gated calcium channels (VGCC) amplify process and induce hormone release
-> all three processes cause a depolarisation of the neuropod cells

Axon-like extensions harbour vesicles with glutamate which is released onto dendrites of the vagal nerve and cause excitatory post-synaptic potentials

Vagus nerve forwards signal to the nucleus tractus solitarius (NTS) in the medulla

Question 10

Central circuits in sugar preference

Answer 10

• NTS (nucleus tractus solitarius) receives input from gut but also oral capitulation (sensation of sweetness and intestinal sugar signalling) as well as olfactory and visual cues (motivational)
• projects to:
  -> hypothalamus
  -> central nucleus of amygdala
  -> locus coeruleus (release of noradrenaline, increases arousal)
  -> dorsal raphe (serotonin increases motivation and mood)
  -> SNc and VTA
• sugar intake increases activity both in mesolimbic and nigrostriatal pathways
• sham-fed rats (taste of sweetness but no glucose ingestion) show mesolimbic activity increase but not nigrostriatal
• left vague nerve has been shown to increase mesolimbic activity
• right vagus nerve increases nigrostriatal activity