A Neural Integration Center for Energy Management in Zebrafish
Devika S. Bodas, Aditi Maduskar, Tarun Kaniganti, Debia Wakhloo, Akilandeswari Balasubramanian, et al.
(see pages 1089–1110)
How organisms manage internal energy stores is remarkably conserved across vertebrates from zebrafish to humans. In this week's Journal, Bodas, Maduskar et al. use the former as a model to understand the neural circuitry that allows for flexible behaviors to serve energy needs. Two diffusive neuropeptides, cocaine- and amphetamine-regulated transcript (CART) and neuropeptide Y (NPY) have opposing effects on feeding behavior: the anorexic CART serves as a satiety signal, while the orexigenic NPY leads to feeding. Despite their well characterized antagonistic activity across many species, it remains unclear how they modulate higher-order circuits to elicit these behaviors. Here, behavioral, neuroanatomical, and activity analysis and pharmacological manipulations revealed complex intracellular signaling that underlies this dynamic plasticity. NPY and CART are expressed in the zebrafish periventricular hypothalamus (analogous to the mammalian arcuate nucleus of the hypothalamus) and in the entopeduncular nucleus (EN; homologous to the mammalian globus pallidus of the basal ganglia). Intracerebroventricular delivery of exogenous CART peptide induced acute anorexia in starved fish. Similarly, intracerebroventricularly delivered glucose induced anorexia, but this was reversed with a neutralizing antibody directed at CART, suggesting that endogenous CART mediated the central effect of glucose on feeding. The expression of CART in neurons of the EN and the periventricular hypothalamic nucleus lateralis tuberis (NLT) fluctuated with feeding state. Immunolabeling and DiI tracing showed that CART-expressing neurons projected from the EN and the periventricular hypothalamus to the dorsomedial telencephalon (Dm), suggesting that Dm neurons may be responsive to energy state via CART signaling. Following intracerebroventricular CART injection or feeding in starved fish, Dm neurons displayed increased phosphorylated ERK, a marker of neuronal activity, suggesting that they did respond to CART signaling that originated in the EN and NLT. Anorexia induced by intracerebroventricular CART injection was attenuated by coinjection of an NMDA receptor (NMDAR) antagonist, as was Dm neuronal activity indicated by phosphorylated ERK, indicating that glutamatergic signaling at NMDAR works in conjunction with CART. Phosphorylation of the NMDAR NR1 by protein kinase C and protein kinase A (PKA), which potentiates the receptor's activity, was required for CART's effects on anorexic behavior and Dm neuronal activity, and greatly sensitized Dm neurons to glutamate. The researchers next examined Dm activity in response to glutamate in whole brains maintained in starved conditions; the neurons were activated by glutamate only when brains were exposed to glucose to mimic fed conditions.
Further experiments showed that the Dm was similarly receptive to NPY signaling of energy depletion. NPY injected intracerebroventricularly increased feeding drive in fed fish, and administration of the NPY receptor Y1R antagonist suppressed biting behavior. Dm neuronal activity was reduced in fish that received intracerebroventricular NPY, and NR1 phosphorylation was diminished in Dm when NPY was coinjected with glucose in starved fish, which the authors determined was due to dephosphorylation by the phosphatase calcineurin and the downregulation of cyclic AMP, which drives PKA activity. Together, the data show that Dm neurons serve to integrate metabolic energy status via opposing CART and NPY signaling.
Snacking zebrafish. Image: Yadhusankar S. (Indian Institute of Science Education and Research Pune, Pune, India).
Decoding Plasticity of Social Behavior in the Accessory Olfactory System
Kelsey E. Zuk, Hillary L. Cansler, Jinxin Wang, and Julian P. Meeks
(see pages 1178–1190)
Mice and other terrestrial mammals rely on chemosensory signals for a plethora of information about other animals—including their species, sex, reproductive status, and even health—that guide social behaviors from mating to aggression. The accessory olfactory system (AOS) forms the hub of this information system. Remarkably, the AOS displays neuroplasticity at the cellular and circuit levels immediately following social interactions. Key players in the AOS are vomeronasal sensory neurons, found in the vomeronasal organ (VNO), which detect chemosensory signals including pheromones. Disruption of these neurons at the cellular level affects social behaviors, but the circuitry of VNO with the rest of the brain remains poorly understood. Studies have examined the role of the AOS's most prevalent neuron: inhibitory GABAergic interneurons called internal granule cells (IGCs), which display increased excitability following social, chemosensory interactions. How these neurons maintain this functional change in response to social interactions was the focus of a study this week from Zuk et al.
The long apical dendrites of the IGCs extend to the external cellular layer to make reciprocal dendrodendritic contacts with excitatory mitral cells, which are analogous to granule cells found in the main olfactory bulb. IGCs undergo structural and functional changes dependent on their electrophysiological experience. The authors investigated whether these changes could be reflected by activity in the expression of the activity-regulated cytoskeleton-associated early-immediate gene Arc in IGCs following aggressive interactions between males. Using a transgenic technology called ArcTRAP (for targeted recombination in active populations), neurons expressing Arc were permanently labeled with tdTomato. Male mice received an injection of 4-OHT to induce Cre (and trigger the labeling), and they were then exposed to a resident–intruder assay in which an unfamiliar male mouse was introduced to the cage for 10 min/d for up to 8 d. This resulted in a significant increase in tdTomato labeling of IGCs. The authors then prepared acute brain slices from the TRAPed and intruder-exposed mice for whole-cell electrophysiological recording. They surmised that a role for accessory olfactory bulb (AOB) IGCs in AOS-mediated behavioral plasticity would require prolonged changes to AOB function following the intruder experience. They examined neurons from slices prepared 1, 3, 5 and 7 d following the intrusion; remarkably, the neurons showed ongoing excitability following the brief social experience even days later. Another experiment showed that subsequent exposure to the same intruder male reinduced Arc expression, and that neuronal excitability persisted and aggressive behavior escalated with additional intruder exposures. To further test the role of IGCs in chemosensory processing, the researchers employed chemogenetic technology using inhibitory DREADDs (designer receptors exclusively activated by designer drugs). Shutting down the activity of IGCs severely curtailed aggressive behaviors in response to intruder mice and the increased neuronal excitability that usually followed. Together, the data show the importance of the IGCs in this early circuit that is critical for memory formation in social behavior.
Footnotes
This Week in The Journal was written by Stephani Sutherland
