Early-Life Neglect Alters Emotional and Cognitive Behavior in a Sex-Dependent Manner and Reduces Glutamatergic Neuronal Excitability in the Prefrontal Cortex

Abstract

Early-life neglect in critical developmental periods has been associated with emotional and cognitive consequences. Maternal separation (MS) has been commonly used as a rodent model to identify the developmental effects of child neglect. However, reports have shown considerable variability in behavioral results from MS studies in both mice and rats. Difficulties in developing reliable child neglect models have impeded advances in identifying the effects of early-life stress. Accumulating evidence shows that neuronal intrinsic excitability plays an important role in information processing and storage in the brain. The prefrontal cortex (PFC) integrates information from many cortical and subcortical structures. No studies to date have examined the impact of early-life stress on glutamatergic neuronal excitability in the PFC. This study aimed to develop a reliable child neglect rat model and observe glutamatergic neuronal excitability in the PFC. An MS with early weaning (MSEW) rat model was developed. Rats were separated from the dam for 4 h per day on postnatal days (PNDs) 2–5 and for 8 h per day on PNDs 6–16 and then weaned on PND 17. A battery of behavioral tests was used to assess anxiety-like behavior, coping behavior, working memory, spatial reference memory, and fear memory. The action potentials (APs) of glutamatergic neuronal membranes were recorded. MSEW resulted in anxiety-like behavior, a passive coping strategy and increased fear memory in male rats and decreased locomotor activity in both sexes. MSEW slightly impaired working memory during non-stressful situations in female rats but did not change spatial reference memory or associative learning under stressful circumstances in either sex. MSEW reduced the number of glutamatergic neuron APs in male rats. Our findings showed that MS with early weaning induced anxiety-like behavior in male rats. The reduced glutamatergic neuronal excitability may be associated with the emotional alteration induced by MSEW in male rats. In addition, MSEW induced adaptive modification, which depended on a non-stressful context.

Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models

“…A newer model than maternal separation alone, maternal separation and early weaning, which may be a more cumulative model of ELA, has produced results that seem to show increased “depressive-like” behavior ( George et al, 2010 ; Montalvo-Ortiz et al, 2016 ; Sun et al, 2021 ) as well as increased behavioral avoidance ( George et al, 2010 ; Carlyle et al, 2012 ; Murthy et al, 2019 ; Sun et al, 2021 ), perhaps reflecting the high comorbidity between MDD and anxiety disorders, but there are still reports showing inconsistent results ( Tan et al, 2017 ; Waters et al, 2022 ). Maternal separation and early weaning studies have generally shown effects in male mice and rats ( George et al, 2010 ; Montalvo-Ortiz et al, 2016 ; Murthy et al, 2019 ; Sun et al, 2021 ), with studies either not examining females or, if so, finding no effects ( Murthy et al, 2019 ; Sun et al, 2021 ). The lack of effects in females may be due to the protective action of certain stages of the estrous cycle in that maternal separation and early weaning mice only shows increased avoidance behavior during diestrus, a time when the ratio of progesterone to estrogen is relatively high ( Laham et al, 2022 ).…”

The Impact of Early Life Stress on the Genetic Influence on Brain and Cognitive Development in Children

“…ELS modulates the expression of the genes responsible for stress physiology, emotion regulation, cognitive control, and learning and memory [6][7][8][9]10 . Animal literature shows a causal effect of ELS on cognition and behaviors [11][12][13][14][15][16][17][18][19][20] and the epi-/genetic mechanisms within the brain [21][22][23][24] . In humans, similar mechanisms may be involved in psychopathology 25,26 , stress physiology 7 , or emotion regulation [27][28][29] .…”

Distinct neuronal excitability alterations of medial prefrontal cortex in early‐life neglect model of rats

“…Liu et al found that oligodendrocytes and myelination impairment of mouse mPFC played a role in social life stress 10 . In previous work, we demonstrated changes in rat medial prefrontal cortex (mPFC) of an early‐life neglect model 11 . Chen et al reported that the excitation/inhibition balance of mPFC layer V also contributed to depression and anxiety‐like emotional disorders of rats 12 .…”

“…10 In previous work, we demonstrated changes in rat medial prefrontal cortex (mPFC) of an early-life neglect model. 11 Chen et al…”