Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition.

Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of microdissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphogenetic protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling. Further, cognitive performance was impaired when the BMP inhibitor, noggin, was knocked down in the DG. Infusion of noggin into the lateral ventricles enhanced DG-dependent cognition while BMP4 infusion led to significant impairments. Embryonic overexpression of noggin resulted in lifelong enhancement of recognition and spatial memory while overexpression of BMP4 resulted in lifelong impairment, substantiating the importance of differences in BMP signaling in wild-type mice. These findings indicate that performance in DG-dependent cognitive tasks is largely determined by differences in levels BMP signaling in the dentate gyrus.

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance.

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD-TAU) and the TDP-43 proteinopathy of FTLD-TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD-TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD-TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.

Activating newborn neurons suppresses depression and anxiety-like behaviors.

The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.

Profound degeneration of wake-promoting neurons in Alzheimer's disease.

INTRODUCTION: Sleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. METHODS: We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. RESULTS: The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. DISCUSSION: WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.