Cerebellar sub-divisions differ in exercise-induced plasticity of noradrenergic axons and in their association with resilience to activity-based anorexia

Abstract

The vermis or “spinocerebellum” receives input from the spinal cord and motor cortex for controlling balance and locomotion, while the longitudinal hemisphere region or “cerebro-cerebellum” is interconnected with non-motor cortical regions, including the prefrontal cortex that underlies decision-making. Noradrenaline release in the cerebellum is known to be important for motor plasticity but less is known about plasticity of the cerebellar noradrenergic (NA) system, itself. We characterized plasticity of dopamine β-hydroxylase-immunoreactive NA fibers in the cerebellum of adolescent female rats that are evoked by voluntary wheel running, food restriction (FR) or by both, in combination. When 8 days of wheel access was combined with FR during the last 4 days, some responded with excessive exercise, choosing to run even during the hours of food access: this exacerbated weight loss beyond that due to FR alone. In the vermis, exercise, with or without FR, shortened the inter-varicosity intervals and increased varicosity density along NA fibers, while excessive exercise, due to FR, also shortened NA fibers. In contrast, the hemisphere required the FR-evoked excessive exercise to evoke shortened inter-varicosity intervals along NA fibers and this change was exhibited more strongly by rats that suppressed the FR-evoked excessive exercise, a behavior that minimized weight loss. Presuming that shortened inter-varicosity intervals translate to enhanced NA release and synthesis of norepinephrine, this enhancement in the cerebellar hemisphere may contribute towards protection of individuals from the life-threatening activity-based anorexia via relays with higher-order cortical areas that mediate the animal’s decision to suppress the innate FR-evoked hyperactivity.

NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise

“…Thirty-two Sprague-Dawley female rats were used for the study and are the same as those used for analysis of noradrenergic axon terminals in the cerebellum (Nedelescu et al 2016) and of α4βδ-GABA(A) receptors in the hippocampus (Aoki et al, ms submitted). The rearing conditions of these rats were identical to those described previously (Aoki et al 2012; Chowdhury et al 2014a, c), except that they were housed at NYU, instead of at the NY Psychiatric Institute.…”

“…While capturing the above symptoms of AN, ABA also reveals individual differences in vulnerability, quantified as the extent of food-restriction-evoked hyperactivity and weight loss (Aoki et al 2014; Chen et al 2016; Chowdhury et al 2013; Wable et al 2015a, b; Nedelescu et al 2016). Since excitability of the hippocampus is strongly linked to stress-induced anxiety (Shen et al 2007), and the extent of food-restriction-evoked anxiety is correlated with wheel running (Wable et al 2015b), we hypothesized that individual differences in wheel running might be influenced by the excitability of hippocampal neurons.…”

“…This study was supported by The Klarman Foundation Grant Program in Eating Disorders Research, R21MH091445–01, R21 MH105846, R01NS066019–01A1, R01NS047557–07A1, NEI Core Grant EY13079, NYU's Research Challenge Fund, NSF-REU 1460880 to CA, YWC, the Fulbright Scholarship to YWC, NYU Dean's Undergraduate Research Fund to AL and JYW, UL1 TR000038 from the National Center for the Advancement of Translational Science (NCATS) to TGC, T32 MH019524 to GSW, NYU Abu Dhabi Fund to CM and R25GM097634–01 to RA. The brain tissue used for this study is the same as that used for another study (Nedelescu et al 2016). Therefore, a portion of the ante mortem weight and wheel running data are presented in both manuscripts.…”

α4βδ‐GABAA receptors in dorsal hippocampal CA1 of adolescent female rats traffic to the plasma membrane of dendritic spines following voluntary exercise and contribute to protection of animals from activity‐based anorexia through localization at excitatory synapses

“…The brains analyzed for this study were the same set of brains used to analyze NMDA receptor expression in the hippocampus (Chen et al, ) and noradrenergic axons in the cerebellum (Nedelescu et al, ). Therefore, data on wheel activity and body weight can be found in these previous publications.…”

“…The rearing conditions for the ABA (i.e., combined food restriction and exercise), the FR (food restriction only), the EX (exercise only), and the CON (control; i.e., neither food restriction nor exercise) animals have been described in a previous publication (Chen et al, ; Nedelescu et al, ) and are described again here briefly (Fig. A).…”