Taxonomic and thematic generalization of safety behaviors.

GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model.

Calcineurin/NFAT1/Smad2 signaling regulates microglial autophagy that contributes to neuroinflammation and cognitive deficit in mice with sepsis-associated encephalopathy.

Sex differences in the impact of trauma on alcohol self-administration.

Exposure to images of post-bushfire disaster impacts fear learning and extinction.

Cleavage of amyloid precursor protein (APP) produces toxic amyloid-beta peptides, which play a critical role in the pathogenesis of Alzheimer's disease. Neuronal loss is a key feature of Alzheimer's disease. Despite the importance of APP in the proliferation of neural progenitors and the survival of adult-born granule cells in the dentate gyrus, little is known about the effect of APP deficiency on neuronal electrophysiological activities and the survival of newly born neurons. Utilizing whole-cell patch-clamp recording in combination with retroviral labeling and immunofluorescent staining in Alzheimer's disease model mice with App knockout (App-/-), we show that APP deficiency increased the number of adult-born granule cells at 4 weeks post-injection, but did not affect their intrinsic excitability or miniature current activity. In contrast, at 10 weeks post-injection, adult-born granule cells showed increased abundance and intrinsic excitability that were associated with abnormal dendritic morphology, increased miniature excitatory- and inhibitory-synaptic transmission, and decreased potassium-chloride-cotransporter 2 expression. Compared with adult-born granule cells at 10 week post-injection, mature granule cells exhibited decreased intrinsic excitability and potassium-chloride-cotransporter 2 expression alongside increased apoptosis in App-/- mice. Additionally, although App-/-mice showed abnormal freezing behavior and elevated mature granule cell activation during contextual fear conditioning, adult-born granule cells were not recruited in either App-/- or wild-type control mice. Taken together, these findings suggest that APP is required for adult-born granule cell maturation and that APP deficiency induces excitotoxicity in adult-born granule cells at 10 weeks post-injection, promoting subsequent apoptosis of mature granule cells.

ABSTRACT Background: Interpersonal trauma is associated with a higher risk of developing symptoms of post-traumatic stress disorder (PTSD) following trauma exposure. PTSD, which is more prevalent among women, is characterised by heightened fear and difficulties regulating it. Although fear regulation deficits in PTSD are well documented, considerable variability exists in how individuals learn and regulate fear. Brain regions involved in fear learning and regulation follow distinct developmental trajectories and are more sensitive to stress at certain timepoints. As exposure to severe stress (e.g. trauma) could influence the development and/or functioning of brain regions involved in fear learning and regulation, the timing of such exposure may potentially induce differential effects. Objective: This study explores the association between the developmental period – childhood (0–11 years), adolescence (12–17 years), adulthood (18 years and older) – during which the first interpersonal trauma occurred, and fear learning and regulation processes in a sample of adult women. Methods: Ninety-five women with a history of interpersonal trauma reported their age at first exposure and underwent a validated two-day fear conditioning and extinction protocol (conditioning and extinction on one day, followed by extinction memory recall 24 h later). Skin conductance responses (SCR) were used to index physiological fear levels. Results: During fear conditioning and extinction, no group differences emerged. During the early phase of extinction memory recall, women whose first trauma occurred during adolescence or adulthood showed higher SCRs than those exposed during childhood (Time × Trauma age group: F(6, 2078.05) = 7.78, p < .001). Conclusion: These findings suggest that the developmental timing of trauma exposure influences fear regulation in adulthood, highlighting potential windows of vulnerability that could inform targeted interventions.

Exposure to low-dose CuO nanoparticles improves fear extinction memory and enhance intrinsic excitability in the infralimbic cortex of male mice.

Antidepressant ketamine via oral gavage impairs fear memory, suppresses 22kHz ultrasonic vocalizations, lowers GluN2A/B expression, and reduces medial habenula activity in rats.

Early treatment with vildagliptin and linagliptin reduces social fear and prevents the onset of comorbid depression in a mouse model of social anxiety disorder.

Neuropathic pain caused contextual fear generalization by reducing RIN1 expression in dorsal hippocampal CA1 pyramidal neurons.

Referenced Summary ParagraphNeuromodulation by acetylcholine (ACh) plays a critical role in reshaping neural dynamics in the neocortex as a function of development, behavioral state, and learning1–6. Prior work suggests cholinergic signaling can act as a gate for the subsequent induction of circuit plasticity3,7,8. However, modification of ACh release could also be a direct mechanism for the expression of cortical plasticity. Here, we combine widefield and 2-photon imaging in head-fixed mice to show that visual fear conditioning leads to a selective, cue-dependent release of ACh in primary visual cortex that enhances visually-evoked neuronal responses via excitation of layer 1 GABAergic interneurons and resulting disinhibition of local excitatory pyramidal neurons. Cholinergic signaling through muscarinic receptors in visual cortex is necessary for both the enhanced visual response and conditioned fear behavior. Our results demonstrate a novel capacity for conditioned release of ACh in sensory cortex to serve as a mechanism for sensory-guided behavioral learning. Rather than acting as a simple gate, cortical neuromodulation may thus play a central role in the expression of learned behavior.

Cognitive reappraisal of conditioned fear: A systematic review.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur, leading to significant impairments in learning and memory. Despite the prevalence of these disorders, existing treatment strategies remain inadequate, necessitating novel approaches targeting underlying neural circuits. This study investigated whether optogenetic stimulation of medial prefrontal cortex subregions could rescue fear extinction deficits in a preclinical model of comorbid PTSD/AUD. We examined the differential roles of the infralimbic (IL) and prelimbic (PL) cortices in modulating extinction learning following combined stress and chronic alcohol exposure. Male and female Wistar rats underwent restraint stress (RS) and chronic intermittent ethanol exposure (CIE), followed by fear conditioning and extinction training. Animals received optogenetic stimulation (ChR2 or eYFP control) targeting either IL or PL cortex immediately prior to each extinction session. Extinction learning rates, days to criterion, and long-term memory retention (21-day spontaneous recovery) were assessed. Combined stress and alcohol exposure significantly impaired extinction learning compared to controls. IL-ChR2 stimulation recovered these extinction deficits in the RS + CIE group, accelerating extinction rates and reducing spontaneous recovery. Conversely, PL-ChR2 stimulation impaired extinction learning in control animals but produced no additional deficits in the already-impaired RS + CIE group, suggesting a ceiling effect. This study identifies the IL cortex as a critical regulator of fear extinction learning following stress and alcohol exposure, demonstrating that targeted circuit activation can overcome extinction deficits characteristic of comorbid PTSD and AUD. These region-specific effects provide important insights into the prefrontal mechanisms governing fear memory processes in pathological states.

Targeting NAAG metabolism restores cognition and synaptic integrity in EcoHIV-infected mice.

The neuroprotective effects of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) have been reported in experimental models of central nervous system (CNS) disorders due to its multi-target actions. Considering the limited efficacy of current treatments for post-traumatic stress disorder (PTSD), this study aimed to investigate the anti-PTSD-like effects of 4-PSQ and its underlying mechanisms during the early developmental stage of single prolonged stress (SPS)-induced PTSD in male and female mice. Following 4h to the SPS exposure, mice were treated with 4-PSQ (5mgkg-1) or vehicle by the intragastric (i.g.) route for three days. The open field test, the elevated plus maze test, and the contextual fear conditioning were performed on days 2 and 3 of the experimental protocol. A short treatment with 4-PSQ reversed the anxiety-like phenotype and the fear memory strength induced by SPS in mice of both sexes. Elevated levels of reactive species (RS) in the cerebral cortex, hippocampus, and hypothalamus of SPS-exposed mice were attenuated by 4-PSQ. Concerning the antioxidant system, males and females exposed to SPS displayed distinct patterns of thiol non-protein (NPSH) levels and the catalase (CAT) activity in the CNS. Notably, the SPS-induced fear memory strength was found to be negatively correlated with Na+, K+-ATPase inhibition and positively correlated with AChE enhancement, underscoring the relevance of both enzymes in the pathogenesis of PTSD. The 4-PSQ treatment normalized both Na+, K+-ATPase and AChE activities. In Summary, the 4-PSQ attenuated the behavioral and sex-specific mechanisms in response to SPS and may be considered as promising molecule for PTSD treatment.

ABSTRACTAging is a complex process that frequently includes cognitive decline with memory loss. In the hippocampus, the number of somatostatin‐positive (Sst+) GABAergic interneurons in the hilar region of the dentate gyrus decreases with age. We previously showed that selective ablation of Sst+ dentate hilar interneurons is sufficient to induce cognitive dysfunction, resulting in a model of hippocampal aging (pseudo‐aged mice). Brain insulin levels and insulin receptor expression also decline with age, and intranasal insulin (INS) has shown promise in improving learning and memory in Alzheimer's disease. Here, we investigated the effects of INS in pseudo‐aged mice with genetically ablated dentate hilar Sst+ interneurons, which were generated by bilateral injection of AAV5‐EF1α‐mCherry‐flex‐dtA into the dentate hilus of Sst‐IRES‐Cre mice (3–5 months old). Following a 3‐week recovery period post‐injection, INS was administered daily for 9 days. INS treatment in pseudo‐aged mice improved working memory in the Y‐maze, recognition memory in the novel object recognition test, and non‐declarative associative memory in trace fear conditioning. At the molecular level, INS reversed the increase in Iba‐1 and pTBK1 expression, indicating attenuation of microglial activation and cGAS–STING pathway signaling, and restored hippocampal BDNF levels. No significant effects of INS were observed in control mice. These findings indicate that INS alleviates memory impairment and reduces neuroinflammation in this hippocampal aging model. Together, the results suggest that intranasal insulin may provide a non‐invasive therapeutic approach for mitigating age‐related cognitive decline by modulating neuroinflammatory and neurotrophic mechanisms.

Alzheimer’s disease (AD), the leading cause of dementia, could potentially be mitigated through early detection and interventions. However, it remains challenging to assess subtle cognitive changes in the early AD continuum. Computational modeling is a promising approach to explain a generative process underlying subtle behavioral changes with a number of putative variables. Nonetheless, internal models of the patient remain underexplored in AD. Determining the states of an internal model between measurable pathological states and behavioral phenotypes would advance explanations about the generative process in earlier disease stages beyond assessing behavior alone. Previously, Gershman et al., 2017b proposed the latent cause model, which provides a normative account of memory modification phenomena in Pavlovian fear conditioning. Here, we assumed the latent cause model as an internal model and estimated internal states defined by the model parameters being in conjunction with measurable behavioral phenotypes. The 6- and 12-month-old App NL-G-F knock-in AD model mice and the age-matched control mice underwent memory modification learning, which consisted of classical fear conditioning, extinction, and reinstatement. The results showed that App NL-G-F mice exhibited a lower extent of reinstatement of fear memory. Computational modeling revealed that the deficit in the App NL-G-F mice would be due to their internal states being biased toward overgeneralization or overdifferentiation of their observations, and consequently, the competing memories were not retained. This deficit was replicated in another type of memory modification learning in the reversal Barnes maze task. Following reversal learning, App NL-G-F mice, given spatial cues, failed to infer coexisting memories for two goal locations during the trial. We concluded that the altered internal states of App NL-G-F mice illustrated their misclassification in the memory modification process. This novel approach highlights the potential of investigating internal states to precisely assess cognitive changes in early AD and multidimensionally evaluate how early interventions may work.

Alzheimer’s disease (AD), the leading cause of dementia, could potentially be mitigated through early detection and interventions. However, it remains challenging to assess subtle cognitive changes in the early AD continuum. Computational modeling is a promising approach to explain a generative process underlying subtle behavioral changes with a number of putative variables. Nonetheless, internal models of the patient remain underexplored in AD. Determining the states of an internal model between measurable pathological states and behavioral phenotypes would advance explanations about the generative process in earlier disease stages beyond assessing behavior alone. Previously, Gershman et al., 2017b proposed the latent cause model, which provides a normative account of memory modification phenomena in Pavlovian fear conditioning. Here, we assumed the latent cause model as an internal model and estimated internal states defined by the model parameters being in conjunction with measurable behavioral phenotypes. The 6- and 12-month-old AppNL-G-F knock-in AD model mice and the age-matched control mice underwent memory modification learning, which consisted of classical fear conditioning, extinction, and reinstatement. The results showed that AppNL-G-F mice exhibited a lower extent of reinstatement of fear memory. Computational modeling revealed that the deficit in the AppNL-G-F mice would be due to their internal states being biased toward overgeneralization or overdifferentiation of their observations, and consequently, the competing memories were not retained. This deficit was replicated in another type of memory modification learning in the reversal Barnes maze task. Following reversal learning, AppNL-G-F mice, given spatial cues, failed to infer coexisting memories for two goal locations during the trial. We concluded that the altered internal states of AppNL-G-F mice illustrated their misclassification in the memory modification process. This novel approach highlights the potential of investigating internal states to precisely assess cognitive changes in early AD and multidimensionally evaluate how early interventions may work.

Sex-dependent role of Neuropeptide-S on anxiety, fear conditioning, and alcohol seeking in alcohol preferring rats.