Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior

Abstract

Early adversity is a risk factor for the development of adult psychopathology. Common across multiple rodent models of early adversity is increased signaling via forebrain Gq-coupled neurotransmitter receptors. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke persistent mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of forebrain excitatory neurons during postnatal life (P2-14), but not in juvenile or adult windows, increased anxiety-, despair-, and schizophrenia-like behavior in adulthood. This was accompanied by an enhanced metabolic rate of cortical and hippocampal glutamatergic and GABAergic neurons. Furthermore, we observed reduced activity and plasticity-associated marker expression, and perturbed excitatory/inhibitory currents in the hippocampus. These results indicate that Gq signaling mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as functional changes in forebrain glutamate and GABA systems, recapitulating aspects of the consequences of early adversity.

Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function

“…In several previous studies, DREADD-induced selective and consecutive stimulation was used as an intervention for damaged optic nerves (Li et al, 2016;Lim et al, 2016), damaged peripheral nerves (Gao et al, 2021;Wu et al, 2020), stressrelated behavior (Chen et al, 2020;Pati et al, 2020), alcohol abuse (Pozhidayeva et al, 2020), pain control (Xu et al, 2021), epilepsy (Desloovere et al, 2019;Goossens et al, 2021), intracerebral hemorrhage (Ling et al, 2020), microglial inflammation (Binning et al, 2020), and b-amyloid deposition (Rodriguez et al, 2020;Yuan and Grutzendler, 2016). In a study stimulating dorsal root ganglia neurons after crush injury (Wu et al, 2020), 4 weeks of repetitive stimulations did not alter the functional scores or axon regeneration, which was significant after 12 weeks.…”

GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders

“…DREADD‐based chemogenetic approaches using both transgenic and viral strategies allow for spatiotemporal regulation of select G protein‐coupled signaling cascades in discrete neuronal populations [138]. It is only relatively recently that DREADD‐mediated chemogenetic strategies have been exploited to address the contribution of Gq‐ and Gi‐mediated signaling pathways in mediating the effects of early stress in programming persistent changes in anxio‐depressive behavioral states [48,139,140].…”

“…In contrast, the Gq-coupled hM3Dq-based DREADD activation of PFC neurons with a pan-neuronal hSyn promoter in pups subjected to the MS paradigm can prevent the emergence of MS-evoked short-term memory impairments and enhanced despair-like behavior [139]. Work from our laboratory has recently demonstrated that chronic chemogenetic activation of Gq signaling in CaMKIIa-positive forebrain excitatory neurons during the early postnatal window (P2-14) is sufficient to program a persistent increase in anxiety and despair-like behavior, accompanied by sensorimotor gating deficits [140]. Adult animals with a history of hM3Dq-based DREADD activation of excitatory forebrain neurons display an altered excitatory/inhibitory balance in cortical circuits as revealed through metabolomic and electrophysiological signatures, phenocopying some of the functional changes associated with preclinical models of psychiatric disorders [140].…”

“…Work from our laboratory has recently demonstrated that chronic chemogenetic activation of Gq signaling in CaMKIIa-positive forebrain excitatory neurons during the early postnatal window (P2-14) is sufficient to program a persistent increase in anxiety and despair-like behavior, accompanied by sensorimotor gating deficits [140]. Adult animals with a history of hM3Dq-based DREADD activation of excitatory forebrain neurons display an altered excitatory/inhibitory balance in cortical circuits as revealed through metabolomic and electrophysiological signatures, phenocopying some of the functional changes associated with preclinical models of psychiatric disorders [140]. The differences noted across the studies described above could arise as a consequence of the specific population of neurons targeted and the neurocircuit that is being regulated (Fig.…”

Chronic hM4Di-DREADD-Mediated Chemogenetic Inhibition of Forebrain Excitatory Neurons in Postnatal or Juvenile Life Does Not Alter Adult Mood-Related Behavior

“…Loss of function of the G q -coupled 5-HT 2A receptor, in particular in the forebrain, is associated with reduced anxiety-like behavior ( Weisstaub, 2006 ), whereas loss of function of the G i -coupled 5-HT 1A receptor during postnatal life, in both forebrain and raphe neurocircuits, has been linked to increased anxiety-like behavior ( Gross et al, 2002 ; Vinkers et al, 2010 ; Richardson-Jones et al, 2010 , 2011 ; Mineur et al, 2015 ). Furthermore, pharmacological blockade of the G i -coupled 5-HT 1A receptor during postnatal life is associated with the emergence of increased anxiety in adulthood ( Vinkers et al, 2010 ; Garcia-Garcia et al, 2014 ; Sarkar et al, 2014 ), whereas pharmacological stimulation of the G q -coupled 5-HT 2A receptors ( Sarkar et al, 2014 ) or enhanced G q signaling driven via chemogenetic activation of excitatory forebrain neurons during postnatal window programs increased anxiety- and despair-like behavior in adulthood ( Pati et al, 2020 ).…”