Bueschke, N. | Search bioRxiv

bioRxiv2025

Hibernation improves neural performance during energy stress in regions across the central nervous system in the American bullfrog

Neuronal signaling requires high rates of ATP production via the oxidative metabolism of glucose. The American bullfrog is intriguing, as this species has typical brain energy requirements for an average vertebrate but modifies synaptic physiology and metabolism after hibernation to maintain function during hypoxia and ischemia. Given the importance of the respiratory system in restoring metabolic homeostasis during emergence from underwater hibernation, work to date has addressed this response in the brainstem respiratory network. Thus, metabolic plasticity has been interpreted as an adaptation used to restart respiratory motor behavior under hypoxic conditions during the transition from skin breathing to air breathing. It remains unclear whether these improvements are specific to the brainstem regions critical for breathing versus a global response within the central nervous system (CNS). To address this question, we recorded neural activity from the spinal cord, forebrain, and brainstem respiratory network in vitro. As expected, hypoxia disrupted the function of each network in control animals. After hibernation, each network improved its activity in hypoxia compared to controls. These results suggest that plasticity that improves neural function during energy stress following hibernation reflects a global response that may impact many behaviors controlled by the CNS and is not limited to regions involved in metabolic homeostasis.

neuroscience↗

bioRxiv2023

Plasticity in the functional properties of NMDA receptors improves motor circuit performance during severe energy stress

Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during energy stress. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs, Lithobates catesbeianus. Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+ permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during energy stress without interfering with its normal role during healthy activity. Significance StatementNeural circuits lose homeostasis during severe energy stress, and NMDA-glutamate receptors play a major role in this response. In contrast, frogs have the remarkable capacity to use plasticity that improves circuit function from minutes to hours during hypoxia, likely as an adaptation to survive emergence from hibernation. We found this occurs, in part, through modification of NMDA receptors that renders them less permeable to Ca2+ and more likely to desensitize during high activity states. These NMDA receptor modifications do not influence normal network function but protect against hyperexcitability caused by hypoxia. This work points to endogenous plasticity mechanisms that improve network function during energy stress without altering circuit function when the brain is well-oxygenated.

neuroscience↗