Perineuronal Nets, Inhibitory Interneurons, and Anxiety-Related Ventral Hippocampal Neuronal Oscillations Are Altered by Early Life Adversity

Abstract

BACKGROUND: In humans, accumulated adverse experiences during childhood increase the risk of anxiety disorders and attention-deficit hyperactivity disorder. In rodents, the ventral hippocampus (vHIP) is associated with anxiety regulation, and lesion of this region alters both anxiety-like behavior and activity levels. Neuronal oscillations in the vHIP of the theta frequency range (4-12 Hz) have been implicated in anxious states and derive in part from the activity of inhibitory interneurons in the hippocampus, some of which are enwrapped with perineuronal nets (PNNs), extracellular matrix structures that regulate plasticity. Here we sought to investigate the associations among early life stress-induced anxiety and hyperactivity with vHIP neuronal oscillations, inhibitory interneurons and PNNs in mice. METHODS: We used repeated maternal separation with early weaning (MSEW) to model accumulated early life adversity in mouse offspring and studied the underlying behavioral and cellular level changes in the vHIP associated with early life adversity. RESULTS: We found increased anxiety-like behavior and activity levels in MSEW adult males, along with increased theta power and enhanced theta-gamma coupling in the vHIP. MSEW mice showed reduced intensity of parvalbumin as well as increased PNN intensity around parvalbumin+ interneurons in the vHIP. We further observed that MSEW increased OTX2, a transcription factor promoting PNN development, in the choroid plexus where it is produced, as well as in parvalbumin+ interneurons, where it is sequestered. CONCLUSION: These findings raise the possibility of causal links among parvalbumin+ interneurons, PNNs, OTX2, and MSEW-induced anxiety and hyperactivity.

Non-cell autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse

“…Our finding that overexpression Otx2 in the ChP can reduce anxiety in the adult suggests that the mechanisms involved in the present hypo-anxiety phenotype either differs from those at work in the maternal separation paradigm or that a link exists between Otx2 expression in the VTA during a critical period (here from P10 to P20) and the ability of the ChP to direct OTX2 to non-cell autonomous target structures. Results from the Gould and colleagues further support this possibility (13). They observed a parallel increase of OTX2 in the ChP and in ventral hippocampus PV cells of mice made hyperanxious through early maternal separation.…”

“…For example, maternal separation of mouse pups between a critical period, ranging from postnatal day 10 (P10) to P20, leads to a social defeat-induced depressive adult phenotype regulated by a transient decrease in Otx2 expression in the VTA (12). In a separate study also involving maternal separationinduced anxiety, it was proposed that Otx2 upregulation in the ChP and OTX2 transfer to ventral hippocampus inhibitory interneurons may participate in the anxiety phenotype (13).…”

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…Surprisingly, prefrontal PV cells have not been thoroughly explored in the context of emotional dysregulations and prefrontal hypoactivity. Some work has highlighted a role of hippocampal PV cells in anxiety (Zou et al, 2016;Murthy et al, 2019), but whether PV cells in the PFC contribute also to mood disorders marked by prefrontal hypoactivity is unclear. Our recent work (Shepard et al, 2016;Shepard and Coutellier, 2018) strongly suggests that plasticity of prefrontal PV neurons contributes to anxiety dysregulations following stress exposure, a known risk factor to mood disorders (Kendler et al, 1999;Duman and Monteggia, 2006;Mineur et al, 2006).…”

Neuron-glia Integrity: Functional Assessment, Molecular Underpinnings, and Implication for Higher Brain Functions

“…The MSEW mice also spent less time in the center of the open field relative to controls (George et al, 2010). Increased anxiety-like behavior and activity levels were also seen in MSEW adult male mice of a recent study (Murthy et al, 2019). However, postnatal maternal separation (MS) demonstrated no clear and consistent effects on behavioral phenotypes in a variety of strains of mice in the other studies (Millstein and Holmes, 2007;Tan et al, 2017).…”