Since our first steps in life, we are forming incidental associations between diverse stimuli across various sensory modalities that influence our future choices and facilitate adaptation to environmental fluctuations. Daily behavior is usually governed by indirect incidental associations among sensory cues that have never been explicitly paired with a reinforcer. This phenomenon, known as higher-order conditioning, can be systematically investigated in laboratory animals through specific behavioral paradigms such as sensory preconditioning protocols. In this study, using “Targeted Recombination in Active Populations” (TRAP2) transgenic mice, we have interrogated which are the brain areas orchestrating the encoding of associations between olfactory and gustatory stimuli and the expression of an aversive odor–taste sensory preconditioning paradigm. We identified neuronal ensembles within the basolateral amygdala specifically activated during odor–taste associations. To demonstrate the causal involvement of this brain region in our sensory preconditioning task, we inhibited it during the preconditioning phase (i.e., incidental associations) using a chemogenetic approach, which caused a clear impairment of the mediated responses. In addition, using retrograde tracers in the basolateral amygdala of TRAP2 mice, we observed that the projections from the lateral entorhinal cortex to the basolateral amygdala are particularly activated during odor–taste associations. Notably, the chemogenetic inhibition of this brain circuit impaired the mediated aversion performance in our sensory preconditioning task. Overall, these findings highlight the amygdala as a pivotal modulator of incidental associations during an aversive sensory preconditioning task and point toward a brain circuit crucially involved in these complex cognitive processes.

Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of hyperphosphorylated tau in neurons and glia. Primary tauopathies are not uncommon in humans but exceptional in other species. We evaluate the clinical, neuropathological, and genetic alterations related to tau pathology in 16 cats aged from 1 to 21 years with different clinical backgrounds. Interestingly, a 10-year-old female cat presented a six-year progressive history of mental status and gait abnormalities. The imaging study revealed generalized cortical atrophy. Due to the poor prognosis, the cat was euthanatized at the age of ten. Neuropathological lesions were characterized by massive neuronal loss with marked spongiosis and associated moderate reactive gliosis in the parietal cortex, being less severe in other areas of the cerebral cortex, and the loss of Purkinje cells of the cerebellum. Immunohistochemical methods revealed a 4R-tauopathy with granular pre-tangles in neurons and coiled bodies in oligodendrocytes. Deposits were recognized with several phospho-site antibodies (4Rtau, tau5, AT8, PFH, tau-P Thr181, tau-P-Ser 262, tau-P Ser 422) and associated with increased granular expression of active tau kinases (p38-P Thr180/Tyr182 and SAPK/JNK-P Thr138/Thr185). The genetic study revealed well-preserved coding regions of MAPT. No similar alterations related to tau pathology were found in the other 15 cats processed in parallel. To our knowledge, this is the first case reporting a primary 4R-tauopathy with severe cerebral and Purkinje cell degeneration in an adult cat with neurological signs starting at a young age.

Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ ⁹ -tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) deficits. Notably, VTA dopamine neuronal activity is required for the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent deficits of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.

Introduction/Objective: The endocannabinoid system has been linked to the pathophysiology of Alzheimer’s Disease (AD), which is accompanied by both neuropathological and behavioral alterations. However, the contribution of this system to these specific processes remains incompletely understood. Here, we investigated the effects of ACEA, a selective agonist of type-1 cannabinoid receptors (CB1R), on repetitive behaviors and amyloid load in the APP/PS1 mouse model of AD. Methods: ACEA for 21 days at 3 months of age, a presymptomatic stage, was administered in male and female APP/PS1 mice and evaluated using non-cognitive behavioral tasks, amyloid load, and CB1R expression. results: We revealed sex-dependent differences in repetitive behaviors. Molecular analyses further demonstrated that ACEA also modulates amyloid burden and CB1R expression in a brain region- and sex-specific manner. Additionally, we characterized distinct amyloid plaque types, offering new insights into the relationship between cannabinoid signaling and AD neuropathology. Results: By using two complementary behavioral paradigms, the splash test and the marble-burying test, we assessed the impact of cannabinoid treatment on male and female mice, revealing sex-dependent differences in repetitive behaviors. Molecular analyses further demonstrated that ACEA also modulates amyloid burden and CB1R expression, considering brain-region- and sex-specific parameters. Additionally, the study characterized distinct amyloid plaque types, offering new insights into the relationship between cannabinoid signaling and AD neuropathology. Discussion: The present findings demonstrate that cannabinoid-based interventions can influence both behavioral outcomes and molecular alterations associated with AD. Importantly, the observed effects appear to depend on biological sex and specific brain regions, emphasizing the need to consider these variables when designing cannabinoid-based therapeutic strategies for AD. Conclusion: Collectively, the study’s findings highlight a modulatory role of cannabinoid drugs in both behavioral and molecular aspects of AD, supporting their potential relevance as therapeutic targets tailored to sex and brain region.