Dysregulation of Hippocampal Autophagic Machinery in the Activity-Based Anorexia Rat Model

11/09/2026

AI Summary

ABA induction persistently dysregulates dorsal hippocampal autophagic machinery, increasing mTOR and ULK1 phosphorylation and TFEB-associated upregulation of Becn1, Ctsb, Beclin-1, LC3-II.
TFEB-driven autophagic activation persists after weight recovery, maintaining elevated Becn1, Ctsb, Beclin-1, and LC3-II levels across ABA stages.
Sustained autophagy co-occurs with increased p62 and Caspase-3, pro-apoptotic signals, potentially driving anorexia-like behaviours and hippocampal cognitive deficits.

AI Summary

We therefore investigated the autophagic machinery in the dorsal hippocampus (dHip), a central hub for energy status modulation and for cognitive processing, in the activity-based anorexia (ABA) rat model, the gold standard in the field.

To analyze autophagic markers in the dHip, adolescent female Sprague-Dawley rats were exposed to 2 h/day of food access + free wheel access (ABA induction) and were sacrificed when they reached the maximum body weight loss allowed concomitantly with an increase in the running activity (acute phase) or following a 7-day recovery period.

Basic summary

J Neurochem. 2026 Sep;170(9):e70549. doi: 10.1111/jnc.70549.

ABSTRACT

In Anorexia Nervosa (AN), the combination of self-induced starvation and hyperactivity may initially recruit the autophagic machinery to sustain the function of energy-demanding brain regions; however, its dysregulation may ultimately contribute to impaired brain function. We therefore investigated the autophagic machinery in the dorsal hippocampus (dHip), a central hub for energy status modulation and for cognitive processing, in the activity-based anorexia (ABA) rat model, the gold standard in the field. To analyze autophagic markers in the dHip, adolescent female Sprague-Dawley rats were exposed to 2 h/day of food access + free wheel access (ABA induction) and were sacrificed when they reached the maximum body weight loss allowed concomitantly with an increase in the running activity (acute phase) or following a 7-day recovery period. Our results show that ABA induction persistently disrupts the regulation of the autophagic machinery. In the acute phase, the ABA condition increases the phosphorylation of mTOR/ULK1 while promoting TFEB-associated mechanisms, enhancing the expression of autophagic markers such as Becn1, Ctsb genes, Beclin-1, and LC3-II proteins. After weight recovery, TFEB-induced activation of Becn1, Ctsb, Beclin-1, and LC3-II remains elevated. In addition, the enhanced expression of autophagic markers is accompanied by an increase in p62 and Caspase3, pro-apoptotic signals. Our findings reveal a sustained activation of autophagy across different stages of the ABA protocol. Rather than functioning exclusively as a survival mechanism, this process could evolve into a driver of aberrant behaviors typical of individuals with AN, such as dieting behaviors and hippocampal-dependent deficits.

PMID:42717733 | DOI:10.1111/jnc.70549

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