Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice

Abstract

Social stress, including bullying during adolescence, is a risk factor for common psychopathologies such as depression. To investigate the neural mechanisms associated with juvenile social stress-induced mood-related endophenotypes, we examined the behavioral, morphological, and biochemical effects of the social defeat stress model of depression on hippocampal dendritic spines within the CA1 stratum radiatum. Adolescent (postnatal day 35) male C57BL/6 mice were subjected to defeat episodes for 10 consecutive days. Twenty-four h later, separate groups of mice were tested on the social interaction and tail suspension tests.Hippocampi were then dissected and Western blots were conducted to quantify protein levels for various markers important for synaptic plasticity including protein kinase M zeta (PKMζ), protein kinase C zeta (PKCζ), the dopamine-1 (D1) receptor, tyrosine hydroxylase (TH), and the dopamine transporter (DAT). Furthermore, we examined the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor subunit GluA2 as well as colocalization with the post-synaptic density 95 (PSD95) protein, within different spine subtypes (filopodia, stubby, long-thin, mushroom) using an immunohistochemistry and Golgi-Cox staining technique. The results revealed that social defeat induced a depression-like behavioral profile, as inferred from decreased social interaction levels, increased immobility on the tail suspension test, and decreases in body weight. Whole hippocampal immunoblots revealed decreases in GluA2, with a concomitant increase in DAT and TH levels in the stressed group. Spine morphology analyses further showed that defeated mice displayed a significant decrease in stubby spines, and an increase in long-thin spines within the CA1 stratum radiatum. Further evaluation of GluA2/PSD95 containing-spines demonstrated a decrease of these markers within long-thin and mushroom spine types. Together, these results indicate that juvenile social stress induces GluA2- and dopamine-associated dysregulation in the hippocampus – a neurobiological mechanism potentially underlying the development of mood-related syndromes as a consequence of adolescent bullying.

Juvenile stress causes reduced locomotor behavior and dendritic spine density in the prefrontal cortex and basolateral amygdala in Sprague–Dawley rats

“…During youth in rats (PD21–PD35), there is little information about the stress effect on synaptic communication, especially on dendritic spine density and dendritic arbor in neurons of limbic regions. Reports from our group and other groups have shown that prenatal and postnatal stress in the rat affects the dendritic tree and dendritic spine density in limbic regions (Ambeskovic et al, ; Gutiérrez‐Rojas et al, ; Íñiguez et al, ; Markham et al, ; Martínez‐Téllez et al, ; Monroy et al, ; Muhammad & Kolb, ; Muhammad et al, ; Suenaga et al, ). For example, prenatal stress in pregnant rats caused by 2‐hrs daily movement restraining from gestational day 11 until delivery caused a significant reduction in dendritic spine density in the CA1 and CA3 region of the hippocampus and nucleus accumbens (NAcc) in the offspring rats at postpubertal age (Martínez‐Téllez et al, ).…”

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway

“…The test induces a robust stress response (9), and the time animals spend immobile relative to the time they spend engaging in escape actions is interpreted as an indicator of their behavioral response to the uncontrollable stressor (7). Critically, prior exposure to stress diminishes behavioral responses during the TST (10). Thus, the TST assays an animal’s behavioral adaptation in response to prior stress exposure, and the test in and of itself induces a strong stress response.…”

Estradiol rapidly increases GluA2‐mushroom spines and decreases GluA2‐filopodia spines in hippocampus CA1

“…In the current studies, a new three‐dimensional analysis of dendritic spines is combined with immunohistochemical staining allowing for colocalization of selected synaptic markers within various spine shapes. Our recent publication using this technique identifies rapid changes within particular spine shapes and changes in synaptic protein markers within these spines after stress and OP memory consolidation (Iniguez et al, ; Sebastian et al, ). Thus, this powerful technique can be utilized to understand E 2 's role in promoting spinogenesis and the synaptic markers within these spines.…”

“…Animals were anesthetized and perfused either 30 or 120 min following E 2 or vehicle treatment as previously reported (Jacome et al, ). Brains were prepared for Golgi‐IHC staining and tertiary, apical spines in CA1 analyzed as previously reported (Iniguez et al, ; Sebastian et al, ). Data were analyzed using one‐way ANOVAs across treatments (vehicle, E 2 30 min, E 2 120 min) × various spine types (stubby, filapodia, long‐thin, mushroom) in combination with Tukey‐corrected t tests for post‐hoc analyses.…”