AMPA receptor x GluN2B

Maternal isolation induces ultrasonic vocalisations (USVs), and playback of these USVs can elicit response calls in receivers. In this study, we investigated whether playback of USVs (38-48 kHz) transmits a state of stress and impairs memory in receivers.

Rat pups were exposed to playback of USVs or modified USVs on postnatal day (PND) 12, and their response calls were recorded. On PND-34, control (Ctrl), maternally separated (MS), USV playback (PB), and modified USV playback (MPB) groups were tested for context-dependent episodic memory. Additionally, molecular markers involved in synaptic plasticity were assessed.

Playback receivers emitted specific response calls: female pups responded with step-up frequencies (39.0-49.7 kHz) to playback of USVs and with downward trills (32-39 kHz) to modified USVs. Rats in the MS and PB groups made more incorrect choices in odour-associated context transitions and long-term memory assessments than those in the Ctrl and MPB groups. Furthermore, corticosterone (CORT) levels were elevated, whereas phosphorylation of extracellular signal-regulated kinase (ERK1/2), N-methyl-D-aspartate (NMDA) receptor subunits (NR2A,2B), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits (GLUR1, GLUR2), postsynaptic density protein 95 (PSD-95), and mature brain-derived neurotrophic factor (mBDNF) were reduced in the MS and PB groups.

USV playback can transmit stress to receivers, alter molecular signalling pathways (pERK1/2, NR2A, NR2B, pGluR1, pGluR2, pPSD95, and BDNF), and impair episodic memory. This model may help identify the neuropathology of early-life stress and the development of behavioural disorders later in life.

Impaired insulin signaling in brain regions such as the hippocampus is thought to contribute to the cognitive deficits associated with conditions such as mild cognitive impairment and Alzheimer's disease. We have previously demonstrated a number of adverse effects in rats with hippocampal‐specific insulin resistance, including hippocampal structural defects, impairments in hippocampal‐dependent learning and memory, neuroplasticity deficits, behavioral despair, and anxiety‐like behaviors. Additionally, we showed that hippocampal‐specific insulin resistance decreased the serine phosphorylation of GluA1 and expression of GluN2B. These effects on postsynaptic glutamate receptors were particularly fascinating, due to the proposed theory of the glutamatergic system as a facilitator of hippocampal synaptic transmission. However, the synaptic effects of hippocampal‐specific insulin resistance with regard to glutamate neurotransmission had yet to be elucidated. To address this question, we examined hippocampal glutamate neurochemistry and expression of glutamatergic synaptic proteins in rats with hippocampal‐specific insulin resistance. We also examined the ability of intranasal insulin to impact glutamatergic synapses. We found decreased synaptic concentrations of glutamate in the hippocampus, likely a result of reduced hippocampal vGluT2 expression. Additionally, hippocampal glutamate efflux was significantly increased in rats with hippocampal‐specific insulin resistance in response to a high (12 U), but not a low (0.072 U), dose of intranasal insulin. Our findings indicate that hippocampal‐specific insulin resistance elicits synaptic plasticity deficits in glutamatergic synapses, which may be overcome by intranasal insulin administration.image

While many individuals experience traumatic events during their lifetimes, only some go on to develop post-traumatic stress disorder (PTSD). This susceptibility and resilience to developing PTSD can be modelled in rodents using the stress-enhanced fear learning (SEFL) procedure, in which rats are exposed to a session of massed, unpredictable footshocks and subsequently assessed on tasks of adaptive fear learning. It has previously been observed that subpopulations of rats are susceptible and resilient to showing the PTSD-like phenotype following SEFL, and that these rats show differences in glutamate receptor expression in the basolateral amygdala. However, it is currently unknown whether structural differences are observed in other brain regions implicated in stress responding and memory. Using the refined SEFL procedure, this study aimed to determine whether expression of GluN2B, GluA1 and GluA2 receptor subunits in the prelimbic and infralimbic cortices, and dorsal hippocampus could be correlated to the SEFL-phenotype or shock experience in male rats. Here we show that following SEFL, differences can be observed in receptor subunit expression in the infralimbic cortex and dorsal hippocampus as a function of shock experience, whilst differences in the prelimbic cortex are associated with susceptibility. Importantly, these structural changes can be observed in male rats that are group-housed and exposed to 13-shocks rather than 15-shocks, indicating that the refined SEFL procedure offers a robust animal analogue of the non-associative fear sensitisation that occurs in PTSD. Future studies using this procedure could pave the way to the eventual development of pharmacological treatments to alleviate or prevent stress-induced psychopathology in susceptible individuals.