Regulator of G protein signaling 6 mediates exerciseinduced recovery of hippocampal neurogenesis, learning, and memory in a mouse model of Alzheimer's disease.

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer's disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer's disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer's disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer's disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6fl/fl; APPSWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer's disease mouse model. We found that voluntary running in APPSWE mice restores their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APPSWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 is expressed in neurons within the dentate gyrus of patients with Alzheimer's disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediates voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APPSWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer's disease.

Sex-specific effects of alcohol on neurobehavioral performance and endoplasmic reticulum stress: an analysis using neuron-specific MANF deficient mice.

Excessive alcohol exposure can cause neurobehavioral deficits and structural alterations in the brain. Emerging research evidence suggests that endoplasmic reticulum (ER) stress plays an important role in alcohol-induced neurotoxicity. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress inducible protein and is responsible to maintain ER homeostasis. MANF is highly expressed in both the developing and mature brain. We have previously shown that MANF deficiency exacerbated alcohol induced neurodegeneration and ER stress in the developing brain. However, little is known regarding the role of MANF in alcohol induced neuronal damage in the adult brain. In this study, we used a neuron-specific MANF knockout (KO) mouse model to investigate the effect of MANF deficiency on acute binge alcohol exposure-induced neurobehavioral deficits and ER stress. Adult male and female MANF KO mice and littermate controls received daily alcohol gavage (5 g/kg) for 10 days and then subjected to a battery of neurobehavioral tests including rotarods, balance beam, DigiGait, open field, elevated plus maze, Barnes maze, and three-chamber sociability task. Female MANF KO animals were more susceptible to alcohol-induced body weight loss. Alcohol exposure did not affect motor function, however female but not male MANF KO mice exhibited an increased locomotor activity in open field test. Learning and memory was not significantly impaired, but it was altered by MANF deficiency in females while it was affected by alcohol treatment in males. Both alcohol-exposed male and female MANF KO mice displayed increased sociability. Alcohol induced the expression of ER chaperones GRP78 and GRP94 and altered the levels of several unfolded protein response (UPR) and neuroinflammation markers in MANF KO mice in a sex-specific manner. The expression of MANF interacting proteins neuroplastin, PDIA1, and PDIA6 was increased in MANF KO mice, and was further induced by alcohol. In conclusion, alcohol exposure and neuronal MANF deficiency interacted to alter neurobehavioral outcomes, ER homeostasis and neuroinflammation in a sex-specific manner.

Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

RGS6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in an Alzheimer's mouse model.

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer's disease (AD). Adult hippocampal neurogenesis (AHN) is reduced in AD patients. Exercise stimulates AHN in rodents and improves memory and slows cognitive decline in AD patients. However, the molecular pathways for exercise-induced AHN and improved cognition in AD are poorly understood. Here, we show that voluntary running in APP SWE mice restores their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus (DG) neuronal progenitors (NPs), which also abolished running-mediated increases in AHN. AHN was reduced in sedentary APP SWE mice versus control mice, with basal AHN reduced by RGS6 deletion in DG NPs. RGS6 expression is significantly lower in the DG of AD patients. Thus, RGS6 mediates exercise-induced rescue of impaired cognition and AHN in AD mice, identifying RGS6 in DG NPs as a potential target to combat hippocampal neuron loss in AD. Teaser: RGS6 expression in hippocampal NPCs promotes voluntary running-induced neurogenesis and restored cognition in APP SWE mice. Field Codes: RGS6, Alzheimer's disease, adult hippocampal neurogenesis, neural precursor cells, dentate gyrus, exercise, learning/memory.

Deletion of the voltage-gated calcium channel, CaV 1.3, causes deficits in motor performance and associative learning.

L-type voltage-gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L-type voltage-gated calcium channel isoforms in the brain is CaV 1.3. Mice lacking CaV 1.3 are reported to have impairments in fear conditioning and depressive-like behaviors, which have been linked to CaV 1.3 function in the hippocampus and amygdala. Genetic variation in CaV 1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with altered motor learning, associative learning and social function. Here, we explored whether CaV 1.3 plays a role in these behaviors. We found that CaV 1.3 knockout mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV 1.3 is also associated with impaired gait adaptation and associative learning on the Erasmus Ladder. We did not observe any impairments in CaV 1.3 knockout mice on assays of anxiety-like, depression-like or social preference behaviors. Our results suggest an important role for CaV 1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.

Unsupervised learning of complex associations in an animal model.

Supervised learning results from explicit corrective feedback, whereas unsupervised learning results from statistical co-occurrence. In an initial training phase, we gave pigeons an unsupervised learning task to see if mere pairing could establish associations between multiple pairs of visual images. To assess learning, we administered occasional testing trials in which pigeons were shown an object and had to choose between previously paired and unpaired tokens. Learning was evidenced by preferential choice of the previously unpaired token. In a subsequent supervised training phase, learning was facilitated if the object and token had previously been paired. These results document unsupervised learning in pigeons and resemble statistical learning in infants, suggesting an important parallel between human and animal cognition.

Chrysippus's pigeon: Exclusion-based responding in an avian model.

Inference by exclusion can be exhibited by deductively responding to new stimuli that are presented in the context of familiar stimuli. We investigated exclusion-based responding in pigeons using a 2-alternative forced-choice discrimination task. In Phase 1, pigeons learned to associate 2 stimuli (A and B) with Response 1 and 2 stimuli (C and D) with Response 2. Following successful acquisition of these stimulus-response pairings, pigeons advanced to Phase 2, in which stimuli A and B were now reassigned to Response 2. Based on their Phase 1 training, pigeons should initially choose Response 1 when presented with A and B in Phase 2 (this response is now incorrect, but the birds would not yet have had the opportunity to learn the new stimulus-response associations). Also, in Phase 2, stimuli E and F-new stimuli replacing stimuli C and D-were concurrently presented and assigned to Response 1. Without prior training, pigeons' initial responding to E and F in Phase 2 should be at chance. However, if the pigeons were to apply an exclusion rule (stimuli E and F stand in opposition to stimuli A and B), then they might initially choose Response 2 for new stimuli E and F because they are concurrently choosing Response 1 for stimuli A and B. If that is the case, then choice accuracy for stimuli E and F should also be below chance. Indeed, our pigeons responded at reliably below chance levels to stimuli E and F, consistent with their exhibiting an exclusion rule-based strategy, which could actually arise from a more mechanical underlying process such as acquired equivalence formation. (PsycINFO Database Record