Highlights d Autophagy induction in hippocampal neurons is required to promote memory formation d Hippocampal autophagy induction enhances activitydependent synaptic plasticity d Inducing autophagy in old hippocampi is sufficient to reverse age-impaired memory d Autophagy integrates the effects of youthful systemic factors in the aged brain

Leucine-rich repeat kinase 2 (LRRK2) and tau have been identified as risk factors of Parkinson's disease (PD). As LRRK2 is a kinase and tau is hyperphosphorylated in some LRRK2 mutation carriers of PD patients, the obvious hypothesis is that tau could be a substrate of LRRK2. Previous reports that LRRK2 phosphorylates free tau or tubulin-associated tau provide direct support for this proposition. By comparing LRRK2 with cdk5, we show that wild-type LRRK2 and the G2019S mutant phosphorylate free recombinant full-length tau protein with specific activity 480- and 250-fold lower than cdk5, respectively. More strikingly tau binds to wt LRRK2 or the G2019S mutant 140- or 200-fold more strongly than cdk5. The extremely low activity of LRRK2 but strong binding affinity with tau suggests that LRRK2 may facilitate tau phosphorylation as a scaffold protein rather than as a major tau kinase. This hypothesis is further supported by the observation that (i) cdk5 or tau coimmunoprecipitates with endogenous LRRK2 in SH-SY5Y cells, in mouse brain tissue, and in human PBMCs; (ii) knocking down endogenous LRRK2 by its siRNA in SH-SY5Y cells reduces tau phosphorylation at Ser396 and Ser404; (iii) inhibiting LRRK2 kinase activity by its inhibitors has no effect on tau phosphorylation at these two sites; and (iv) overexpressing wt LRRK2, the G2019S mutant, or the D1994A kinase-dead mutant in SH-SY5Y cells has no effect on tau phosphorylation. Our results suggest that LRRK2 facilitates tau phosphorylation indirectly by recruiting tau or cdk5 rather than by directly phosphorylating tau.

Hemispheric lateralization is a fundamental organizing principle of nervous systems across taxonomic groups with bilateral symmetry. The mammalian hippocampus is lateralized anatomically, physiologically, and chemically; however, functional asymmetries are not yet well understood. Imaging studies in humans have implicated the left and right hippocampus in specialized processing. However, it is not clear if lateralized activity occurs in the rodent hippocampus. c-Fos imaging in animals provides a measure of neuronal activity with a resolution at the level of single cells. The aim of the present study was to determine whether lateralized activity-dependent c-Fos expression occurs in the rodent hippocampus. To understand functional lateralization of hippocampal processing, we compared interhemispheric expression of c-Fos in the dentate gyrus (DG), a structure involved in encoding new experiences, in mice that ran on a wheel, encoded a novel object, or remained in home cages. We found that wheel running (WR) induced the greatest amount of DG c-Fos expression in both hemispheres, with no difference between hemispheres. Object exploration (OB) resulted in left-lateralized DG c-Fos expression, whereas control (CON) mice were not lateralized. We then sought to determine whether differential consideration of hemispheres might influence the conclusions of a study by simulating common cell quantitation methods. We found that different approaches led to different conclusions. These data demonstrate lateralization of neuronal activity in the mouse DG corresponding to the experience of the animal and show that differentially considering hemisphere leads to alternative conclusions.

The estrous cycle is a potent modulator of neuron physiology. In rodents,in vivoventral tegmental area (VTA) dopamine (DA) activity has been shown to fluctuate across the estrous cycle. While the behavioral effect of fluctuating sex steroids on the reward circuit is well studied in response to drugs of abuse, few studies have focused on the molecular adaptations in the context of stress and motivated social behaviors. We hypothesized that estradiol fluctuations across the estrous cycle acts upon the dopaminergic activity of the VTA to alter excitability and stress response. We used whole-cell slice electrophysiology of VTA DA neurons in naturally cycling, adult female C57BL/6J mice to characterize the effects of the estrous cycle and the role of 17β-estradiol on neuronal activity. We show that the estrous phase alters the effect of 17β-estradiol on excitability in the VTA. Behaviorally, the estrous phase during a series of acute variable social stressors modulates subsequent reward related behaviors. Pharmacological inhibition of estrogen receptors in the VTA prior to stress during diestrus mimics the stress susceptibility found during estrus while increased potassium channel activity in the VTA prior to stress reverses stress susceptibility found during estrus as assessed by social interaction behavior. This study identifies one possible potassium channel mechanism underlying the increased DA activity during estrus and reveals estrogen dependent changes in neuronal function. Our findings demonstrate that the estrous cycle and estrogen signaling changes the physiology of DA neurons resulting in behavioral differences when the reward circuit is challenged with stress.SIGNIFICANCE STATEMENT:The activity of the ventral tegmental area encodes signals of stress and reward. Dopaminergic activity has been found to be regulated by both local synaptic inputs as well as inputs from other brain regions. Here, we provide evidence that cycling sex steroids also plays are role in modulating stress sensitivity of dopaminergic reward behavior. Specifically, we reveal a correlation of ionic activity with estrous phase, which influences the behavioral response to stress. These findings shed new light how estrous cycle may influence dopaminergic activity primarily during times of stress perturbation.

The bed nucleus of the stria terminalis (BNST) is a highly heterogeneous limbic forebrain structure that serves as a relay connecting autonomic, neuroendocrine and behavioral function. It can be divided into over 16 individual subregions with distinct neuronal subpopulations based on receptors, transmitters, and neuropeptides. Specifically, the BNST projection to the ventral tegmental area (VTA), the dopamine hub of the brain, has been shown to have a crucial role in the stress response. However, in mice there is a lack of unbiased data on the functional diversity of this sub-population which serves as an upstream input to the VTA. The dopaminergic neurons in the VTA modify their ion channel activity and intrinsic membrane properties to adapt to stress in part from inputs from BNST projections. Therefore, we aimed to perform a multi-component characterization of the functional diversity of the BNST-VTA pathway. We studied the passive and active electrophysiological properties of virally identified population of BNST neurons that project to the VTA. We used a comprehensive series of in vitro recordings of electrophysiological variables and performed hierarchical clustering to determine the functional diversity of the projection neurons in the BNST-VTA pathway. Our study revealed four subpopulations in the BNST-VTA pathway, all of which differ in their activation profiles and likely have distinct inputs and function in the VTA. Our results will help resolve the discord in interpretation of the various roles of this electrophysiologically diverse projection and builds a foundation for understanding how the different neuronal types integrate signals.