In the mouse brain, olfactory information is transmitted to the olfactory cortex via olfactory bulb (OB) projection neurons known as mitral and tufted cells. Although mitral and tufted cells share many cellular characteristics, these cell types are distinct in their somata location and in their axonal and dendritic projection patterns. Moreover, mitral cells consist of heterogeneous subpopulations. We have previously shown that mitral cells generated at different embryonic days differentially localize within the mitral cell layer (MCL) and extend their lateral dendrites to different sublayers of the external plexiform layer (EPL). Here, we examined the axonal projection patterns from the subpopulations of OB projection neurons that are determined by the timing of neurogenesis (neuronal birthdate) to understand the developmental origin of the diversity in olfactory pathways. We separately labeled early-generated and late-generated OB projection neurons using in utero electroporation performed at embryonic d...

Alzheimer’s disease (AD) starts decades before clinical symptoms appear. Low-glucose utilization in regions of the cerebral cortex marks early AD. To identify these regions, we conducted a voxel-wise meta-analysis of previous studies conducted with positron emission tomography that compared AD patients with healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, and middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes that show spatial correlation across the cerebral cortex between their expression and this hypometabolism. Of the six brains in the Atlas, one demonstrated a strong spatial correlation between gene expression and hypometabolism. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when comparing th...

Larval zebrafish possess a number of molecular and genetic advantages for rigorous biological analyses of learning and memory. These advantages have motivated the search for novel forms of memory in these animals that can be exploited for understanding the cellular and molecular bases of vertebrate memory formation and consolidation. Here, we report a new form of behavioral sensitization in zebrafish larvae that is elicited by an aversive chemical stimulus [allyl isothiocyanate (AITC)] and that persists for ≥30 min. This form of sensitization is expressed as enhanced locomotion and thigmotaxis, as well as elevated heart rate. To characterize the neural basis of this nonassociative memory, we used transgenic zebrafish expressing the fluorescent calcium indicator GCaMP6 ([Chen et al., 2013][1]); because of the transparency of larval zebrafish, we could optically monitor neural activity in the brain of intact transgenic zebrafish before and after the induction of sensitization. We found a distinct brain area,...

Alzheimer’s disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, we used a genetic and pharmacological approach to evaluate the beneficial effects of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila , other RAS components are not conserved. We show that captopril, an ACE-I, and losartan, an ARB, can suppress a rough eye phenotype and brain cell death in flies expressing a mutant human C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human A β 42 and losartan significantly rescues memory deficits. However, neither drug a...

Microglia are resident macrophages that are critical for brain development and homeostasis. Microglial morphology is dynamically changed during postnatal stages, leading to regulating synaptogenesis and synapse pruning. Moreover, it has been well known that the shape of microglia is also altered in response to the detritus of the apoptotic cells and pathogens such as bacteria and viruses. Although the morphologic changes are crucial for acquiring microglial functions, the exact mechanism which controls their morphology is not fully understood. Here, we report that the FAT atypical cadherin family protein, FAT3, regulates the morphology of microglial cell line, BV2. We found that the shape of BV2 becomes elongated in a high-nutrient medium. Using microarray analysis, we identified that FAT3 expression is induced by culturing with a high-nutrient medium. In addition, we found that purinergic analog, hypoxanthine, promotes FAT3 expression in BV2 and mouse primary microglia. FAT3 expression induced by hypoxant...

Throughout adulthood, the dentate gyrus continues to produce new granule cells, which integrate into the hippocampal circuitry. New neurons have been linked to several known functions of the hippocampus, including learning and memory, anxiety and stress regulation, and social behavior. We explored whether transgenic reduction of adult-born neurons in mice would impair social memory and the formation of social dominance hierarchies. We used a conditional transgenic mouse strain [thymidine kinase (TK) mice] that selectively reduces adult neurogenesis by treatment with the antiviral drug valganciclovir (VGCV). TK mice treated with VGCV were unable to recognize conspecifics as familiar 24 h after initial exposure. We then explored whether reducing new neurons completely impaired their ability to acquire or retrieve a social memory and found that TK mice treated with VGCV were able to perform at control levels when the time between exposure (acquisition) and reexposure (retrieval) was brief. We next explored wh...

Humans adapt to mechanical perturbations such as forcefields (FFs) during reaching within tens of trials. However, recent findings suggested that this adaptation may start within one single trial, i.e., online corrective movements can become tuned to the unanticipated perturbations within a trial. This was highlighted in previous works with a reaching experiment in which participants had to stop at a via-point (VP) located between the start and the goal. An FF was applied during the first and second parts of the movement and then occasionally unexpectedly switched off at the VP during catch trials. The results showed an after-effect during the second part of the movement when participants exited the VP. This behavioral result was interpreted as a standard after-effect, but it remained unclear how it was related to conventional trial-by-trial learning. The current study aimed to investigate how long do such changes in movement representations last in memory. For this, we have studied the same reaching task ...

The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is currently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegenerative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism(s). An important fact is that the brain is capable of using ketone bodies for fuel. Another critical point is that glucose’s functions span beyond its role as an energy substrate, and in most of these functions, glucose is irreplaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.

During cochlear development, the Notch ligand JAGGED 1 (JAG1) plays an important role in the specification of the prosensory region, which gives rise to sound-sensing hair cells and neighboring supporting cells (SCs). While JAG1’s expression is maintained in SCs through adulthood, the function of JAG1 in SC development is unknown. Here, we demonstrate that JAG1 is essential for the formation and maintenance of Hensen’s cells, a highly specialized SC-subtype located at the edge of the auditory epithelium. Using Sox2CreER/+ :: Jag1loxP/loxP mice of both genders, we show that Jag1 deletion at the onset of differentiation, at embryonic day 14.5, disrupted Hensen’s cell formation. Similar loss of Hensen’s cells was observed when Jag1 was deleted after Hensen’s cell formation at postnatal day (P) 0/P1 and fate-mapping analysis revealed that in the absence of Jag1, some Hensen’s cells die, but others convert into neighboring Claudius cells. In support of a role for JAG1 in cell survival, genes involved in mitocho...

Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signalling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca2+ responses in astrocytes of the rat brainstem were blocked by (i) antagonists of connexin channels, connexin 43 (Cx43) blocking peptide Gap26, or Cx43 gene knockdown; (ii) antagonists of TRPV4 channels; (iii) antagonist of P2Y1 receptors for ATP; and (iv) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and Cx43 channels in astrocytes. Dye loadi...