Hypocretins and biogenic amines and their cognate receptors densely accumulate in infralimbic structures including the amygdala, hippocampus, and insular, cingulated, and prefrontal cortex. Apart from convergent, direct excitatory effects of hypocretins on nonspecific thalamic relay neuronsl35 and intracortically projecting layer 6b neurons/36 the orchestration of aminergic, glutamatergic, and GABAergic signals provides a powerful mechanism promoting cortical activation, plasticity, and probably memory functions.l29,l33,l37
The prefrontal cortex is an organizer of attentional set shifting, cognitive appraisal, executive fuctions, and autonomic responses to hypoglycemia, hunger, and drowsiness.35,36,93 Hypocretins facilitate the release of catecholamines56,58 and through glutamatergic mechanisms they induce calcium transients in dendritic spines of distinct prefrontal thalamocortical synapses.138 Action potential backfiring in presynaptic afferents of non-specific thalamic neurons135,138 is considered to promote synchronous behavioral state-dependent ensemble activity.68
Likewise, in the hippocampus, an integrator of multimodal sensorimotor functions and neuroendocrine-autonomic control,139 hypocretins, again in concert with biogenic amines, promote synchronous network activity and synaptic plasticity.30,31,64,65 Hcrt receptors are expressed in all subregions of the hippocampus but most densely in the dentate gyrus,30 the main entrance pathway conveying information from the entorhinal cortex to the hippocampus.
Injection of Hcrt1 into the dentate gyrus or locus coeruleus, a preferred target of hypocretinergic modulation,32123 promotes the induction of glutamate-dependent LTP in vivo. Co-application of adrenergic receptor antagonists in the locus coeruleus blocked Hcrt-induced synaptic plasticity in the dentate gyrus.128 Immunoreactivity for the native Hcrt-1 peptide is largely restricted to Schaffer-collateral-CA130 and septohippocampal pathways. The latter "gates" hippocampal disinhibition and theta rhythm through convergent facilitatory actions of hypocretins and biogenic amines.39,85 141 Theta rhythm is a behavioral state-dependent large scale oscillatory brain activity associated with exploratory behavior, novelty, stress, REM sleep, and bidirectional, spike-timing-dependent plasticity.68 In contrast, so-called Schaffer-collateral axons provide excitatory drive from the CA3 region, an autoassociative sharp wave generator,68 to the CA1 region, the major output of the hippocampus. Sharp waves, in contrast to theta rhythm, occur during consummatory behavior, rest, immobility, and slow wave sleep, thus representing an off-line state of the brain promoting hippocampal-cortical dialogue and memory consolidation. Histamine and hypocretins are powerful modulators of these oscillations in vitro2130 and in vivo.316465
Brief bath application of Hcrt1 to hippocampal slices triggers theta-rhythm patterned sharp wave-concurrent field burst activity in the CA3 region, capable to induce a slow onset long-term potentiation of synaptic transmission (LTPOX) in CA1 region.30142 Consistent with the absence of direct hypocretin effects on hippocampal neurons in culture1, as well as with the mechanisms of activation of thalamocortical synapses138 this form of plasticity is expressed presynaptically. More important, it requires coordinated signaling of glutamate, GABA, noradrenaline, and acetylcholine (Figure 6).
Analysis of the molecular signature of LTPOX revealed a requirement for co-activation of multiple plasticity-related kinases and synthesis of new proteins.142 Blockade of a few decisive signal transduction pathways, including metabotropic glutamate mGluR1 receptors, CaMKII, and PKA, or mTOR-dependent protein synthesis converted LTPOX into a long-term depression (LTD), indicating that hypocretins, in line with theta-patterned stimulus conditions, promote bidirectional modifications of synaptic strength. Interestingly, the direction of Hcrt-induced plasticity is dependent on the age of the animals, suggesting a developmental switch60 and explaining seemingly contradictory findings in rats.143 The molecular signature of hypocretin-induced synaptic plasticity matches that of conditioned taste aversion.132
Collectively, hypocretins, in concert with biogenic amines, promote protein synthesis-dependent LTP, as well as protein synthesis-independent LTD.30 This binary mode of action may promote network bistability6 and homeostatic functions60, outbalancing electrical activities, while in parallel providing set points for structural rewiring and rescaling of neural circuits.
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