Muscle secretes factors during exercise that enhance cognition. Myokine Cathepsin B (Ctsb) is linked to memory function, but its role in neurodegenerative disease is unclear. Here we show that AAV-vector-mediated Ctsb overexpression in skeletal muscle in an Alzheimer's Disease (AD) mouse model (APP/PS1), improves motor coordination, memory function and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment modifies hippocampal, muscle and plasma proteomic profiles to resemble that of wildtype controls. Conversely, in wildtype mice, Ctsb expression causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. In AD mice, Ctsb treatment increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult hippocampal neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes, and reduces inflammatory responses. In muscle, Ctsb expression elevates protein translation in AD mice, whereas in wildtype mice mitochondrial proteins decrease. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we generated a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.

Adult neurogenesis occurs in the dentate gyrus (DG) of the rodent hippocampus throughout life, producing new granule cells (GCs) that migrate from a stem cell niche called the subgranular zone (SGZ) into the adjacent granule cell layer (GCL). Seizures associated with temporal lobe epilepsy alter adult neurogenesis and promote the formation of hyperexcitable circuits. Stem cell therapies for treating intractable seizure disorders are based on the premise that transplantation of GABAergic interneurons will strengthen inhibitory connections within the hippocampus and reduce hyperexcitability. Grafts of medial ganglionic eminence (MGE)-derived fetal GABAergic progenitors into the DG of adult mice with pilocarpine-induced TLE have been shown to suppress spontaneous recurrent seizures. In addition, the transplanted cells formed functional inhibitory synaptic connections with hippocampal neurons, including adult-born GCs. However, it is unknown whether MGE grafts change adult-born GC connectivity. To address this question, we compared the first-order monosynaptic inputs to adult-born GCs in TLE mice with or without MGE-derived interneuron grafts. Here we show that TLE increased excitatory inputs from endogenous hippocampal, entorhinal cortex, and medial septum/diagonal band neurons onto adult-born GCs. In contrast, in TLE mice with grafts, these excitatory inputs were reduced, coinciding with transplanted GABAergic interneuron innervation of adult-born GCs. These findings indicate that GABAergic interneuron transplantation into the dentate gyrus may prevent epilepsy-associated alterations in the connectivity of adult-born GCs.