Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity.

Functional output of the hippocampus, a brain region subserving memory function, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular events involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in plasticity processes in the hippocampus, a role that decreases with brain aging as expression is lost. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. Consistent with the accumulation of extracellular matrix (ECM) in the hippocampus we observe with aging, we find that TIMP2 acts to reduce accumulation of ECM around synapses in the hippocampus. Moreover, its deletion results in hindrance of newborn neuron migration through a denser ECM network. A novel conditional TIMP2 knockout (KO) model reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.

APOE4 confers transcriptomic and functional alterations to primary mouse microglia.

Common genetic variants in more than forty loci modulate risk for Alzheimer's disease (AD). AD risk alleles are enriched within enhancers active in myeloid cells, suggesting that microglia, the brain-resident macrophages, may play a key role in the etiology of AD. A major genetic risk factor for AD is Apolipoprotein E (APOE) genotype, with the ε4/ε4 (E4) genotype increasing risk for AD by approximately 15 fold compared to the most common ε3/ε3 (E3) genotype. However, the impact of APOE genotype on microglial function has not been thoroughly investigated. To address this, we cultured primary microglia from mice in which both alleles of the mouse Apoe gene have been humanized to encode either human APOE ε3 or APOE ε4. Relative to E3 microglia, E4 microglia exhibit altered morphology, increased endolysosomal mass, increased cytokine/chemokine production, and increased lipid and lipid droplet accumulation at baseline. These changes were accompanied by decreased translation and increased phosphorylation of eIF2ɑ and eIF2ɑ-kinases that participate in the integrated stress response, suggesting that E4 genotype leads to elevated levels of cellular stress in microglia relative to E3 genotype. Using live-cell imaging and flow cytometry, we also show that E4 microglia exhibited increased phagocytic uptake of myelin and other substrates compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential enrichment of genes in interferon signaling, extracellular matrix and translation-related pathways was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Together, our results suggest E4 genotype confers several important functional alterations to microglia even prior to myelin challenge, providing insight into the molecular and cellular mechanisms by which APOE4 may increase risk for AD.

Social housing enhances acquisition of task set independently of environmental enrichment: A longitudinal study in the Barnes maze.

Human studies suggest that healthy social relationships benefit cognition, yet little is known about the underlying neural mechanisms of this protective effect. In rodents, studies on acute isolation and environmental enrichment (EE) confirm the importance of social exposure. Despite the widely recognized importance of sociality, however, rodent models have yet to explore the independent contributions of social housing divorced of other forms of enrichment. This study dissociates the effects of social and physical enrichment on spatial learning and memory from adulthood to old age. Rats were placed in either single or group housing, provided with ample enrichment, and tested at three time points on several phases/versions of the Barnes maze (BM) (standard, retention probes, variable location, and reversal). We found that sustained social housing enhanced cognitive flexibility, as evidenced by superior acquisition of task set (standard BM), adaptability to a new task set (variable BM), and improved reversal learning (reversal BM). Long-term retention (BM retention probes) of spatial memory was unaffected by housing conditions. Recent studies from our lab, including this report, are the first to show that social housing confers cognitive benefits beyond those of physical enrichment. Importantly, our experimental design is ideal for exploring the neural underpinnings of this socially induced cognitive protection. Understanding how sociality influences cognition will be invaluable to translational models of aging, neuropsychiatric disease, and neurological injury.

Youth-associated platelet-derived chemokine reverses brain aging through neuroimmune mechanisms.

Age-related loss of brain function has been seen as inevitable, yet recent work leveraging the systemic environment challenges this notion. Schroer et al. demonstrate that youth-associated platelet factor 4 (PF4) partially restores brain function in aged mice while reducing peripheral immune dysfunction, supporting periphery-based approaches to treat age-associated brain disorders.

Social vs. Nonsocial Housing Differentially Affects Perseverative Behavior in Rats (Ratus norvegicus).

Perseverance, also commonly referred to as grit or industriousness, is the continued effort exerted to complete goal-directed tasks. Many factors, such as stress, can contribute to perseverative behavior, but the role of sociality on perseverance in animal models has not been studied. In this experiment, perseverance was measured in Long-Evans rats; half of which were socially housed (SH) and the other half were nonsocially housed (NSH). Rats were placed in a continuous T-maze; one arm of the maze contained an unobstructed low value reward and the other arm contained a high value reward blocked by a barrier that progressively increased in height across testing sessions. We will hereon refer to the low value reward and high value reward as the low reward and the high reward, respectively. Perseverative behavior was assessed by time spent interacting with the barrier and trials were characterized as either adaptive perseverative trials (high reward obtainment) and maladaptive perseverative trials (low reward obtainment after abandoning attempts to overcome the high reward barrier). SH and NSH rats were equally proficient at overcoming a physical barrier to obtain a higher-valued reward, but the NSH rats spent more time interacting with the barriers during maladaptive perseverative trials than SH rats. NSH rats thus exhibited prolonged efforts to overcome the barrier only to ultimately travel to the low reward option. In contrast, SH rats selected the low reward option earlier in the trial and did not maladaptively perseverate without obtaining the high reward. Putative evidence for increased perseverance in NSH rats is explained in the context of maladaptive perseverative behavior rather than perseverance per se. Increased adaptability and acquisition of task-set in SH rats suggests a role of social housing in advantageous decision making.