Exposure to early-life stress (ELS) can persistently modify neuronal circuits and functions, and contribute to the expression of misfolded and aggregated proteins that are hallmarks of several neurodegenerative diseases. The healthy brain is able to clear dysfunctional proteins through the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Accumulating evidence indicates that impairment of these pathways contributes to enhanced protein aggregation and neurodegeneration. While stress is a known precipitant of neurological decline, few specific mechanistic links underlying this relationship have been identified. We hypothesized that neonatal maternal separation (MatSep), a well-established model of ELS, has the ability to alter the levels of UPS and ALP components in the brain, and thus has the potential to disrupt proteostasis. The expression of proteostasis-associated protein markers was evaluated by immunoblotting in the hippocampus and cortex of adult Wistar rats that were previously subjected to MatSep. We observed multiple sex- and MatSep-specific changes in the expression of proteins in the ALP, mitophagy, and UPS pathways, particularly in the hippocampus of adult animals. In contrast, MatSep had limited influence on proteostasis marker expression in the cortex of adult animals. Our results indicate that MatSep can selectively modify the intracellular protein degradation machinery in ways that may impact the development and progression of neurodegenerative disease.
Previous studies have shown that stress can induce inflammatory responses in the body, and contribute to deficits in learning and memory. Whether or not this is a causal relationship, however, is not well understood. This study investigated immune and inflammatory changes induced by stress; we hypothesized that cytokine secretion and white blood cell (WBC) profiles would be altered by stress exposure. Adult male rats were restrained for 30 min, and brain tissue and blood harvested 2h after the end of the stress. Flow cytometry was used to count T‐ and B‐cells from the WBC fraction of the blood. Blocks of brain tissue containing hippocampal and hypothalamic regions were dissected, homogenized in PBS, and a Milliplex MAP kit used to measure multiple cytokines in these samples and in the plasma. Acute stress did not significantly alter cytokine levels in any of our tissues. A significant reduction was seen, however, in the number of B‐cells in acutely stressed rats compared to controls (p<0.05). In conclusion, our data support our hypothesis in part, as changes in immune or inflammatory factors were seen after acute stress. Future studies will confirm and extend these data, determine the role of B‐cells during stress, and examine these responses in repeatedly stressed animals.Supported by: 8G12MD007592
Previous studies have shown that a repeated 6‐hr restraint stress causes hippocampal plasticity and a shift in the profile of activated neurons in the basolateral amygdala (BLA), suggesting an alteration in mechanisms that direct learning and memory in repeatedly stressed individuals. The purpose of this study was to determine whether a less severe stress exposure induces similar adaptations and whether this response is sex‐specific. Adult male and female rats were acutely or repeatedly restrained for 30 min/d; brain sections were stained immunohistochemically for Fos and calbindin (CB), a marker of GABAergic neurons, and quantified in the BLA to determine cellular activation along with phenotypic profile. Significance was determined by t‐test, with p<0.05 considered significant. We hypothesized that repeated stress would decrease the number of BLA neurons expressing both Fos and CB, compared to control or acutely stressed rats, but that these effects would not differ between sexes. In support of our hypothesis, the number of CB‐expressing neurons in the BLA did not differ according to sex or stress treatment. However, we did not find any significant differences in the number of activated (Fos‐expressing) CB neurons in either sex in response to stress. Therefore, this specific type of GABAergic influence from the BLA to the hippocampus may not be affected by this level of stress.Supported by: 8G12MD007592
Early-life adversity (ELA) can induce persistent neurological changes and increase the risk for developing affective or substance use disorders. Disruptions to the reward circuitry of the brain and pathways serving motivation and emotion have been implicated in the link between ELA and altered adult behavior. The molecular mechanisms that mediate the long-term effects of ELA, however, are not fully understood. We examined whether ELA in the form of neonatal maternal separation (MatSep) modifies behavior and synaptic protein expression in adults. We hypothesized that MatSep would affect dopaminergic and glutamatergic signaling and enhance sensitivity to methamphetamine (Meth) reward or increase anxiety. Male Wistar rats were subjected to MatSep for 180 min/d on postnatal days (PND) 2–14 and allowed to grow to adulthood (PND 60) with no further manipulation. The hippocampus (Hipp), medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and caudate putamen (CPu) were isolated from one subgroup of animals and subjected to Western blot and protein quantitation for tyrosine hydroxylase (TH), α-synuclein (ALPHA), NMDA receptor (NMDAR), dopamine receptor-1 (D1) and –2 (D2), dopamine transporter (DAT), and postsynaptic density 95 (PSD95). Separate group of animals were tested for anxiety-like behavior and conditioned place preference (CPP) to Meth at 0.0, 0.1, and 1.0 mg/kg doses. MatSep rats displayed an increase in basal levels of anxiety-like behavior compared to control animals. MatSep rats also demonstrated CPP to Meth, but their responses did not differ significantly from controls at any drug dose. Increased NMDAR, D2, and ALPHA expression was observed in the NAc and CPu following MatSep; D2 and ALPHA levels were also elevated in the mPFC, along with DAT. MatSep rats had reduced D1 expression in the mPFC and Hipp, with the Hipp also showing a reduction in D2. Only the CPu showed elevated TH and decreased DAT expression levels. No significant changes were found in PSD95 expression in MatSep rats. In conclusion, ELA is associated with long-lasting and region-specific changes in synaptic protein expression that diminish dopamine neurotransmission and increase anxiety-like behavior in adults. These findings illustrate potential mechanisms through which ELA may increase vulnerability to stress-related illness.
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