Restricted accessResearch articleFirst published online 2025-10
Boosting the ventrolateral periaqueductal gray-ventral tegmental area pathway by disinhibition of group II mGluRs alleviates chronic restraint stress-induced depression-like behavior in mice
Major depressive disorder (MDD) is a prevalent psychiatric illness, significantly contributing to disability and suicide rates. While dysfunctions in neurotransmission, notably monoaminergic transmission, are commonly attributed to MDD, involvement of the glutamatergic system in comorbid depressive disorders suggests its potential as a target for antidepressant therapy. Despite evidence of diminished glutamatergic neuron activity in the midbrain ventrolateral periaqueductal gray (vlPAG) in rodent models of depression—which projects to the ventral tegmental area (VTA), a region regulating depression-like behaviors—the precise neurocircuit mechanisms within the vlPAG remain unclear.
Methods:
To investigate dysregulation of glutamatergic transmission in the vlPAG and its role in depression-like behavior, we combined behavioral testing, pharmacological manipulation, retrograde tracing, and electrophysiological recording in male C57BL/6 mice.
Results:
Mice receiving intravlPAG infusion of the mGlu2/3 receptor antagonist LY341495 exhibited reversal of depression-like behaviors. Chronic restraint stress (CRS) elicited depression-like behavior, whereas intravlPAG administration of LY341495 reversed these behaviors. VTA-projecting vlPAG neurons exhibited reduced frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and decreased neuronal excitability. Blocking mGlu2/3 receptors, which act as autoreceptors inhibiting glutamate release, in the vlPAG rescued these effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione prevented LY341495-induced reversal of depression-like behaviors.
Conclusions:
This provides the first direct evidence that blockade of mGlu2/3 receptors in the vlPAG ameliorates depression-like behavior, highlighting their role in regulating vlPAG-VTA neurocircuits implicated in MDD pathophysiology.
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