Elsevier

Biological Psychiatry

Volume 85, Issue 12, 15 June 2019, Pages 1011-1020
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2019.02.021Get rights and content

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 lesions in this region alter 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 known to regulate plasticity. 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 cellular and electrophysiological changes in the vHIP that are associated with excessive anxiety and hyperactivity.

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-positive interneurons in the vHIP. We further observed that MSEW increased orthodenticle homeobox protein 2, a transcription factor promoting PNN development, in the choroid plexus, where it is produced, as well as in parvalbumin-positive interneurons, where it is sequestered.

Conclusions

These findings raise the possibility of causal links among parvalbumin-positive interneurons, PNNs, orthodenticle homeobox protein 2, and MSEW-induced anxiety and hyperactivity.

Section snippets

Maternal Separation With Early Weaning

Twenty litters of C57BL/6J mice from two breeding cohorts were exposed to one of two rearing conditions at postnatal day 2 (P2): 1) nonhandled controls; or 2) maternal separation for 4 hours daily from P2 to P5 and 8 hours daily from P6 to P16. Pups in the latter group were weaned at P17 while control litters were weaned at the typical age of P21 (11). At age P60 to P70, mice underwent behavior testing (see Supplemental Methods).

Behavior

Anxiety and activity testing were carried out as detailed in the

MSEW Results in Increased Anxiety-like Behavior in Males in the Elevated Plus Maze

We observed increased anxiety-like behavior in two cohorts of MSEW male mice compared with male controls. MSEW mice in cohort one showed increased anxiety in the elevated plus maze (EPM), with a significantly lower percentage of entries into the open arms (Figure 1B). MSEW mice in cohort one also spent significantly more time in the closed arms (Figure 1C). To verify the reliability of this manipulation, we repeated behavioral tests with a second cohort of mice. MSEW mice from cohort two also

Discussion

Our findings confirmed previous studies that adult male mice subjected to MSEW exhibit an increase in anxiety-like behavior and activity levels (11). We further showed that MSEW increased theta power in the vHIP when in a novel environment, but not in a familiar environment, as well as increased phase amplitude coupling between theta and gamma in both settings. The analysis of cellular subtypes within the vHIP revealed that MSEW resulted in reduced densities of PV+ and SST+ interneurons in the

Acknowledgments and Disclosures

This work was supported by a C.V. Starr Fellowship (to SM) and National Institute of Mental Health Grant No. R01MH117459-01 (to EG).

We thank Adam T. Brockett and Patrick K. Monari for their advice and help with surgeries and experiments and Brandy A. Briones and Elise C. Cope for their helpful comments on the manuscript.

The authors report no biomedical financial interests or potential conflicts of interest.

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