Voluntary Wheel Running Exercise Evoked by Food-Restriction Stress Exacerbates Weight Loss of Adolescent Female Rats But Also Promotes Resilience by Enhancing GABAergic Inhibition of Pyramidal Neurons in the Dorsal Hippocampus

Abstract

Adolescence is marked by increased vulnerability to mental disorders and maladaptive behaviors, including anorexia nervosa. Food-restriction (FR) stress evokes foraging, which translates to increased wheel running exercise (EX) for caged rodents, a maladaptive behavior, since it does not improve food access and exacerbates weight loss. While almost all adolescent rodents increase EX following FR, some then become resilient by suppressing EX by the second–fourth FR day, which minimizes weight loss. We asked whether GABAergic plasticity in the hippocampus may underlie this gain in resilience. In vitro slice physiology revealed doubling of pyramidal neurons’ GABA response in the dorsal hippocampus of food-restricted animals with wheel access (FR + EX for 4 days), but without increase of mIPSC amplitudes. mIPSC frequency increased by 46%, but electron microscopy revealed no increase in axosomatic GABAergic synapse number onto pyramidal cells and only a modest increase (26%) of GABAergic synapse lengths. These changes suggest increase of vesicular release probability and extrasynaptic GABAA receptors and unsilencing of GABAergic synapses. GABAergic synapse lengths correlated with individual’s suppression of wheel running and weight loss. These analyses indicate that EX can have dual roles—exacerbate weight loss but also promote resilience to some by dampening hippocampal excitability.

Effects of adolescent experience of food restriction and exercise on spatial learning and open field exploration of female rats

“…By comparison, food restriction, imposed exactly as described in this report, increases NR2B subunit expression nearly 100% at presynaptic locations, relative to CONs (Chen et al, 2017) without increases in the expression of GABAergic axon terminals (Chowdhury, Wable, et al, 2019) or α4βδ-GABA A Rs (Aoki et al, 2012). Increases in presynaptic NMDARs have been implicated to enhance glutamate release (Bidoret, Ayon, Barbour, & Casado, 2009;Dore et al, 2017), thereby adding to the postsynaptic mechanism of boosting excitatory synaptic transmission.…”

“…The room lights turned on every day at 7 a.m. and turned off at 7 p.m. Sixteen animals each were assigned to CON, FR, EX and EX + FR groups. The rearing conditions of these rats were identical to those described previously (Chowdhury, Wable, et al, 2019). These rats were delivered as eight cohorts of 8 animals each.…”

“…In the EX + FR group at P47-48, the beneficial effects of food restriction and exercise on cognitive performance may have been occluded by the increased GABAergic innervation of pyramidal neurons, which has been shown in the hippocampus of adolescent female mice (Chowdhury, Wable, et al, 2013) and rats (Chowdhury, Wable, et al, 2019), based on electron microscopic analyses performed immediately following the end of the food restriction period (P44). Rats and mice that have undergone EX + FR also exhibit increased expression of α4/δ-containing GABA A receptors at excitatory axo-spinous synapses of the hippocampus (Aoki et al, 2012;Aoki et al, 2014;Aoki et al, 2017;Chen, Wable, Chowdhury, & Aoki, 2016).…”

Voluntary wheel running promotes myelination in the motor cortex through Wnt signaling in mice

“…running wheel. Wheel running was entirely voluntary, and no means were used to promote or ensure activity [18]. Control mice were housed in similar cages except that the wheel was locked.…”

Suppression of food restriction‐evoked hyperactivity in activity‐based anorexia animal model through glutamate transporters GLT‐1 at excitatory synapses in the hippocampus

“…Ordinary wild‐type mice voluntarily engage in wheel running, even in the wild, indicating that wheel running is intrinsically rewarding (Meijer & Robbers, 2014). However, within 24 hr of restricting food access, laboratory animals' wheel running begins to increase and quickly becomes maladaptive, such that the animals continue running even during the limited hours of food availability (Aoki et al., 2017; Chowdhury et al., 2013, 2019; Santiago et al., in press; Smits et al., 2008). Thus, the animals voluntarily food‐restrict, which is a behavior most often associated with AN.…”