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

Abstract

G-protein-coupled receptors (GPCRs) coupled to G i signaling, in particular downstream of monoaminergic neurotransmission, are posited to play a key role during developmental epochs (postnatal and juvenile) in shaping the emergence of adult anxiodepressive behaviors and sensorimotor gating. To address the role of G i signaling in these developmental windows, we used a CaMKIIα-tTA::TRE hM4Di bigenic mouse line to express the hM4Di-DREADD (designer receptor exclusively activated by designer drugs) in forebrain excitatory neurons and enhanced G i signaling via chronic administration of the DREADD agonist, clozapine- N -oxide (CNO) in the postnatal window (postnatal days 2–14) or the juvenile window (postnatal days 28–40). We confirmed that the expression of the HA-tagged hM4Di-DREADD was restricted to CaMKIIα-positive neurons in the forebrain, and that the administration of CNO in postnatal or juvenile windows evoked inhibition in forebrain circuits of the hippocampus and cortex, as indicated by a decline in expression of the neuronal activity marker c-Fos. hM4Di-DREADD-mediated inhibition of CaMKIIα-positive forebrain excitatory neurons in postnatal or juvenile life did not impact the weight profile of mouse pups, and also did not influence the normal ontogeny of sensory reflexes. Further, postnatal or juvenile hM4Di-DREADD-mediated inhibition of CaMKIIα-positive forebrain excitatory neurons did not alter anxiety- or despair-like behaviors in adulthood and did not impact sensorimotor gating. Collectively, these results indicate that chemogenetic induction of G i signaling in CaMKIIα-positive forebrain excitatory neurons in postnatal and juvenile temporal windows does not appear to impinge on the programming of anxiodepressive behaviors in adulthood.

Activation of the rostral nucleus accumbens shell by optogenetics induces cataplexy-like behavior in orexin neuron-ablated mice

“…In mice, DREADDs are available for long-term neuronal manipulation, from 5-10 min to approximately 9 h 25,26 , which has been used to study mood-related behavior [27][28][29] . Because cataplexy is a very short event (10-s to several min) 1,30 , long-term activation by DREADD cannot distinguish between the triggering role and facilitating role of elsewhere initiated signals.…”

The lateral habenula is required for maternal behavior in the mouse dam

“…But maternal behavior is ill-suited to alternating saline days with DREADD-agonist days, since there are multiple latent variables, namely hormonally-mediated maternal behavior onset, learned maternal behavior acquisition, and changing pup needs, operating on a multiday timescale in the early postpartum period. Thus, we opted for chronic LHb inactivation (Benoit et al, 2022; Canetta et al, 2022; Tiwari et al, 2022) and injected the LHb of half the animals with an active inhibitory-DREADD virus (AAV2-hSyn-hM4D(Gi)-mCherry and the other half with a control virus (AAV2-hSyn-mCherry). From E17-LD4, all mice received 4x daily injections with Agonist-21, a designer ligand for the hM4D(Gi) metabotropic receptor (Figure 3A).…”

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

“…Further, a recent report indicates that postnatal chemogenetic activation of Emx1-positive forebrain neurons led to a reduction of social behavior and enhanced grooming behavior, associated with a decreased cortical neuronal excitability and enhanced E/I ratio (Medendorp et al ., 2021). In contrast, a chemogenetic inhibition of forebrain excitatory neurons during the postnatal window did not influence adult anxiety and despair-like behavior (Tiwari et al ., 2022). In this regard, our findings that postnatal chemogenetic activation of PV-positive inhibitory interneurons can program a reduction in anxiety and despair-like behavior, suggests that targeting specific neuronal subpopulations in key limbic microcircuits during this window can program differing behavioral outcomes for mood-related behaviors.…”