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Stress Reduces Extracellular ATP in the Prefrontal Cortex and Activates the Prefrontal Cortex–Lateral Habenula Pathway for Depressive-like Behavior

      Major depressive disorder (MDD) is a common and devastating mental disorder that causes feelings of sadness and anhedonia (loss of pleasure or interest in activities), lack of motivation, cognitive deficits, and vegetative symptoms. It is the leading cause of disability around the world, affecting 4.4% of world’s population. Although the etiology of MDD remains unclear, recent research has begun to unravel its pathophysiological mechanisms. Arguably, three brain regions stand out as most involved in MDD—the prefrontal cortex (PFC), the hippocampus, and the amygdala—of which the PFC seems to be most consistently impaired in MDD (
      • Pizzagalli D.A.
      • Roberts A.C.
      Prefrontal cortex and depression.
      ). Pathological findings include reductions in PFC volume, synapse numbers and dendrite complexity, and dysfunction of glutamatergic and GABAergic (gamma-aminobutyric acidergic) transmission in the medial PFC (mPFC). In accordance with these findings, mPFC glutamate levels were reported to be higher in women with postpartum depression (
      • McEwen A.M.
      • Burgess D.T.A.
      • Hanstock C.C.
      • Seres P.
      • Khalili P.
      • Newman S.
      • et al.
      Increased glutamate levels in the medial prefrontal cortex in patients with postpartum depression.
      ), while decreased levels of glutamatergic metabolites in the mPFC were observed in patients with depression (
      • Moriguchi S.
      • Takamiya A.
      • Noda Y.
      • Horita N.
      • Wada M.
      • Tsugawa S.
      • et al.
      Glutamatergic neurometabolite levels in major depressive disorder: A systematic review and meta-analysis of proton magnetic resonance spectroscopy studies.
      ). Data from mouse studies are also inconsistent, as both hyperexcitability and decreased excitability have been reported to occur in the PFC of depression-inducing stress models. One reason for the apparently conflicting observations may be the diversity of neurons in the mPFC that are known to project to different subcortical regions, including the lateral habenula (LHb), dorsal raphe nucleus (DRN), nucleus accumbens, basal lateral amygdala, periaqueductal gray, medial dorsal thalamus, and dorsal striatum, many of which have been implicated in MDD. For example, activation of the PFC-DRN pathway was shown to alleviate depressive-like behavior, whereas activation of the mPFC-LHb pathway impaired passive coping behavior in the forced swim test. It is plausible that each group of mPFC projection neurons is uniquely impacted under stress and contributes to different aspects of depression pathology. Outstanding questions in the field include the following: How are these circuits impaired in depression? Are they regulated in a circuit-specific manner? Is the regulation via a top-down or a bottom-up mechanism? And importantly, what are the molecular mechanisms?
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