Convergent energy state-dependent antagonistic signalling by CART and NPY modulates the plasticity of forebrain neurons to regulate feeding in zebrafish

Abstract

Dynamic re-configuration of circuit function subserves the flexibility of innate behaviours tuned to physiological states. Internal energy stores adaptively regulate feeding-associated behaviours by integrating opposing hunger and satiety signals at the level of neural circuits. Across vertebrate lineages, the neuropeptides CART and NPY have potent anorexic and orexic functions, respectively, and show energy state-dependent expression in interoceptive neurons. However, how the antagonistic activities of these peptides modulate circuit plasticity remain unclear. Using behavioural, neuroanatomical and activity analysis in adult zebrafish, along with pharmacological interventions, we show that CART and NPY activities converge on a population of neurons in the dorsomedial telencephalon (Dm). While CART facilitates glutamatergic neurotransmission at the Dm, NPY dampens the response to glutamate. In energy-rich states, CART enhances NMDA receptor (NMDAR) function by PKA/PKC mediated phosphorylation of the NR1 subunit of the NMDAR complex. Conversely, starvation triggers NPY-mediated reduction in phosphorylated NR1 via calcineurin activation and inhibition of cAMP production leading to reduced responsiveness to glutamate. Our data identify convergent integration of CART and NPY inputs by the Dm neurons to generate nutritional state-dependent circuit plasticity that is correlated with the behavioural switch induced by the opposing actions of satiety and hunger signals.

Senescence and its Effect on Aging and Dementia

“…The presence of senescent astrocytes has been also found in cultures obtained from the postmortem AD brain tissues. Intriguingly, upregulated expression and βgalactosidase activity, and SASP are identified in these senescent astrocytes Likewise, in human brain slices, a relationship between senescent microglia with AD is seen that includes the identification of senescent disease-associated microglia phenotype (DAM) along with intracellular/phagocytic Aβ particles [39,40,41]. Some researchers also demonstrate that Aβ oligomers induce senescence in aged-microglia cultures from AD brains [42].…”