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The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory formation are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 by extracellular perineuronal nets which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.One-Sentence SummaryEpisodic-like memory precision requires maturation of hippocampal inhibitory interneurons by the extracellular matrix.

The brain organizes experiences into memories that can be used to guide future behavior. Hippocampal CA1 population activity may reflect the retrieval of predictive models that contain information about future events, but little is known about how these kinds of memories develop with experience. We trained mice on a series of tone discrimination problems with or without a common statistical structure to observe how memories are formed and updated during learning. Mice that learned structured problems integrated their experiences into a predictive model that contained the solutions to upcoming novel problems. Retrieving the model during learning improved discrimination accuracy and facilitated learning by decreasing the amount of new information that needed to be acquired. Using calcium imaging to track the activity of thousands of CA1 neurons during learning on this task, we observed the emergence of a persistent hippocampal ensemble at the same time that mice formed a predictive model of their environment. This ensemble was reactivated during training and incorporated new neuronal activity patterns from each training problem. Interestingly, the degree to which mice reactivated the ensemble was related to how well their model predicted the content of the current problem, ensuring that the model was only updated with congruent information. In contrast, mice trained on unstructured problems did not form a predictive model or engage a persistent ensemble. These results show how hippocampal activity supports building predictive models by organizing newly learned information according to its congruence with existing memories.

Summary: Alcohol use is a major risk factor for death and disease worldwide and alcohol-related harms appear to be more prevalent in rural and remote, relative to urban, communities. This Review synthesised international research on rural–urban disparities in hazardous and harmful alcohol use and risk factors for these outcomes within rural and remote communities. 280 studies from 49 countries were included in the Scoping Review. Most studies (60%) found rural, relative to urban, residence to be associated with an increased likelihood of hazardous alcohol use or alcohol-related harm. This proportion increased between 1990 and 2019 and varied by country, age group, and outcome type, being highest in Australia, among young adults, and for more severe alcohol-related harms, such as drink driving and alcohol-related suicide. Improved public health strategies to reduce the burden of alcohol use in rural communities are required but their efficacy will depend on how well they are tailored to the unique needs of the region they are implemented in.

Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein UbG76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.

Background Mechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored. Objective This study examines whether DBS of the medial septal nucleus (MSN) can regulate gene expression of AAV-transduced neurons in a brain region anatomically remote from the stimulation target: the hippocampal dentate gyrus. Methods Rats underwent unilateral hippocampal injection of an AAV vector with c-Fos promoter-driven expression of TdTomato (TdT), followed by medial septal nucleus (MSN) electrode implantation. Rodents received no stimulation, 7.7 Hz (theta), or 130 Hz (gamma) DBS for 1 hour one week after surgery. In a repeat stimulation experiment, rodents received either no stimulation, or two 1 hour MSN DBS over 2 weeks. Results No significant differences in hippocampal TdT expression between controls and acute MSN DBS were found. With repeat DBS we found c-Fos protein expression was induced and we could detect increased TdT with either gamma or theta stimulation. Conclusion We demonstrate that viral vector-mediated gene expression can be regulated spatially and temporally using DBS. Control of gene expression by DBS warrants further investigation into stimulation-responsive promoters for clinical applications.

As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson’s disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a ‘switch’ that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.