In the adult murine brain, neural stem cells (NSCs) can be found in two main niches: the dentate gyrus (DG) and the subventricular zone (SVZ). In the DG, NSCs produce intermediate progenitors (IPs) that differentiate into excitatory neurons, while progenitors in the SVZ migrate to the olfactory bulb (OB), where they mainly differentiate into inhibitory interneurons. Neurogenesis, the process of generating new neurons, persists throughout life but decreases dramatically with aging, concomitantly with increased inflammation. Although many cell types, including microglia, undergo significant transcriptional changes, few such changes have been detected in neural progenitors. Furthermore, transcriptional profiles in progenitors from different neurogenic regions have not been compared on a single-cell level, and little is known about how they are affected by aging-related inflammation. We have generated a single cell RNA sequencing dataset enriched for IPs, which revealed that most aged neural progenitors only acquire minor transcriptional changes. However, progenitors set to become excitatory neurons decrease faster than others. In addition, a population in the aged SVZ, not detected in the OB, acquired major transcriptional activation related to immune responses. This suggests that differences in age related neurogenic decline between regions is not due to tissue differences but rather cell type specific intrinsic transcriptional programs, and that subset of neuroblasts in the SVZ react strongly to age related inflammatory cues.

Desmoplakin (Dsp) is a component of desmosomal cell-cell junctions that interacts with the cadherin complex and cytoskeletal intermediate filaments. In addition to its function as an adhesion component, Dsp is involved in various biological processes, such as gene expression, differentiation, and migration. Dsp is specifically expressed in the hippocampal dentate gyrus (DG) in the central nervous system. However, it is unclear how Dsp impacts hippocampal function and its related behaviors. Using an adeno-associated virus knockdown system in mice, we provide evidence that Dsp in the DG maintains hippocampal functions, including neuronal activity and adult neurogenesis, and contributes to anxiolytic-like effects. Dsp protein is mostly localized in mature granule cells in the adult DG. Dsp knockdown in the DG resulted in a lowered expression of an activity-dependent transcription factor FosB, and an increased expression of mature neuronal markers, such as calbindin. In addition, the suppression of Dsp decreases serotonin responsiveness at the DG output mossy fiber synapses and alters adult neurogenic processes in the subgranular zone of the DG. Moreover, DG-specific Dsp knockdown mice showed an increase in anxiety-like behaviors. Taken together, this research uncovers an unexplored function for Dsp in the central nervous system and suggests that Dsp in the DG may function as a regulator to maintain proper neuronal activation and adult neurogenesis, and contribute to the adaptation of emotion-related behavior.

Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.

Astrocytes display context-specific diversity in their functions and respond to noxious stimuli between brain regions. Astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on ATP generation and Ca2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca2+ signaling in astrocytes, the extent of this regulation in astrocytes from different brain regions remains unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for astrocyte function, however, possible diverse responses to this noxious stimulus between brain areas were not reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI expressing the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two brain regions, the dorsolateral striatum and dentate gyrus, and we show that Mito-PstI induces astrocytic mtDNA loss in vivo, but with remarkable brain-region-dependent differences on mitochondrial dynamics, Ca2+ fluxes, and astrocytic and microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca2+ signaling in a brain-region-selective manner.

General anesthesia can impact a patient\'s memory and cognition by influencing hippocampal function. The CA1 and dentate gyrus (DG), serving as the primary efferent and gateway of the hippocampal trisynaptic circuit facilitating cognitive learning and memory functions, exhibit significant differences in cellular composition, molecular makeup, and responses to various stimuli. However, the effects of isoflurane-induced general anesthesia on CA1 and DG neuronal activity in mice are not well understood. In this study, utilizing electrophysiological recordings, we examined neuronal population dynamics and single-unit activity (SUA) of CA1 and DG in freely behaving mice during natural sleep and general anesthesia. Our findings reveal that isoflurane anesthesia shifts local field potential (LFP) to delta frequency and reduces the firing rate of SUA in both CA1 and DG, compared to wakefulness. Additionally, the firing rates of DG neurons are significantly lower than CA1 neurons during isoflurane anesthesia, and the recovery of theta power is slower in DG than in CA1 during the transition from anesthesia to wakefulness, indicating a stronger and more prolonged impact of isoflurane anesthesia on DG. This work presents a suitable approach for studying brain activities during general anesthesia and provides evidence for distinct effects of isoflurane anesthesia on hippocampal subregions.

Memories of events are linked to the contexts in which they were encoded. This contextual linking ensures enhanced access to those memories that are most relevant to the context at hand, including specific associations that were previously learned in that context. This principle, referred to as encoding specificity, predicts that context-specific neural states should bias retrieval of particular associations over others, potentially allowing for the disambiguation of retrieval cues that may have multiple associations or meanings. Using a context-odor paired associate learning paradigm in mice, here, we show that chemogenetic manipulation of dentate gyrus ensembles corresponding to specific contexts reinstates context-specific neural states in downstream CA1 and biases retrieval toward context-specific associations.

The integration of spatial information in the mammalian dentate gyrus (DG) is critical to navigation. Indeed, DG granule cells (DGCs) rely upon finely balanced inhibitory neurotransmission in order to respond appropriately to specific spatial inputs. This inhibition arises from a heterogeneous population of local GABAergic interneurons (INs) that activate both fast, ionotropic GABAA receptors (GABAAR) and slow, metabotropic GABAB receptors (GABABR), respectively. GABABRs in turn inhibit pre- and postsynaptic neuronal compartments via temporally long-lasting G-protein-dependent mechanisms. The relative contribution of each IN subtype to network level GABABR signal setting remains unknown. However, within the DG, the somatostatin (SSt) expressing IN subtype is considered crucial in coordinating appropriate feedback inhibition on to DGCs. Therefore, we virally delivered channelrhodopsin 2 to the DG in order to obtain control of this specific SSt IN subpopulation in male and female adult mice. Using a combination of optogenetic activation and pharmacology, we show that SSt INs strongly recruit postsynaptic GABABRs to drive greater inhibition in DGCs than GABAARs at physiological membrane potentials. Furthermore, we show that in the adult mouse DG, postsynaptic GABABR signaling is predominantly regulated by neuronal GABA uptake and less so by astrocytic mechanisms. Finally, we confirm that activation of SSt INs can also recruit presynaptic GABABRs, as has been shown in neocortical circuits. Together, these data reveal that GABABR signaling allows SSt INs to control DG activity and may constitute a key mechanism for gating spatial information flow within hippocampal circuits.

Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.

Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory, but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we find that male and female mice previously housed in an enriched environment, which triggers an increase in neurogenesis, have increased spatial information encoding in the dentate gyrus. Ablating adult neurogenesis blocks the effect of enrichment and lowers spatial information, as does the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreases the calcium activity of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast with previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory.

Our study investigated the innate immune response to Toxoplasma gondii infection by assessing microglial phenotypic changes and sickness behavior as inflammatory response markers post-ocular tachyzoite instillation. Disease progression in Swiss albino mice was compared with the previously documented outcomes in BALB/c mice using an identical ocular route and parasite burden (2 × 105 tachyzoites), with saline as the control. Contrary to expectations, the Swiss albino mice displayed rapid, lethal disease progression, marked by pronounced sickness behaviors and mortality within 11-12 days post-infection, while the survivors exhibited no apparent signs of infection. Comparative analysis revealed the T. gondii-infected BALB/c mice exhibited reduced avoidance of feline odors, while the infected Swiss albino mice showed enhanced avoidance responses. There was an important increase in microglial cells in the dentate gyrus molecular layer of the infected Swiss albino mice compared to the BALB/c mice and their respective controls. Hierarchical cluster and discriminant analyses identified three microglial morphological clusters, differentially affected by T. gondii infection across strains. The BALB/c mice exhibited increased microglial branching and complexity, while the Swiss albino mice showed reduced shrunken microglial arbors, diminishing their morphological complexity. These findings highlight strain-specific differences in disease progression and inflammatory regulation, indicating lineage-specific mechanisms in inflammatory responses, tolerance, and resistance. Understanding these elements is critical in devising control measures for toxoplasmosis.