Biology subjects

Dranovsky, A.

Publications and source records attributed to Dranovsky, A..

4 recordsLinked to original sources

bioRxiv2018

Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Adult neurogenesis is impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in a progressing decline in hippocampal acetylcholine and the slow emergence of profound working memory deficits. These deficits were accompanied by compensatory rewiring of cholinergic dentate gyrus inputs such that ventrally projecting neurons were recruited by the dorsal projection. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

neuroscience↗

bioRxiv2018

Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum et al., 2014), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.

neuroscience↗

bioRxiv2018

iPSC-derived neurons as a tool for probing molecular pharmacology of antipsychotic action.

BackgroundInduced pluripotent stem cell derived neurons (iPSC-Neurons) provide a potential way to investigate molecular mechanisms of psychotropic drug action in human neurons. Until now such studies have relied on animal models or artificial expression systems in transfected cells.\n\nMethodsInduced pluripotent stem cells were subjected to a dual SMAD inhibition differentiation protocol. Resulting neurons were examined using qPCR, immunocytochemistry, viral transduction, and calcium imaging.\n\nResultsHere we report the presence of target receptors for antipsychotic drugs in human iPSC-neurons. A cortical neuronal differentiation protocol resulted in cells that expressed D2, 5HT2A, and other target receptors. Moreover, stimulation with glutamate, dopamine, or the 5HT2A agonist DOI evoked calcium transients. We analyzed single cell responses, and found cells with signature response profiles to these ligands. In addition, pre-incubation of iPSC-neurons with clozapine altered the proportion of cells that responded to glutamate or DOI in a subpopulation of neurons.\n\nConclusionsOur results support the use of iPSC-neuron single cell pharmacology for studying how psychotropic medications modulate neuronal responses. Because these cells can be derived directly from patients, results derived from using iPSC-neurons have immediate relevance for personalized medicine.\n\nSignificance StatementThe current study examines the feasibility of using induced pluripotent stem cells from patients to generate neurons and study psychopharmacology. This article is broadly intended to inform the readership on the key points of iPSC-derived neurons as a system and how it can be used to understand antipsychotic pharmacology for potential clinical application. The specific advances include 1) demonstrating the presence of receptors targeted by antipsychotics on iPSC-derived neurons; 2) Using single cell analysis to identify human neurons with distinct responses to receptor modulation; and 3) Demonstrating that clozapine modulates glutamatergic and serotonergic responses in distinct human neuronal populations.

pharmacology and toxicology↗

bioRxiv2018

Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood

Deficits in arousal and stress responsiveness span numerous psychiatric developmental disorders including depression and anxiety. Arousal is supported by norepinephrine (NE) released from locus coeruleus (LC) neurons onto cortical and limbic areas. During development, the NE system matures in concert with increased exploration of the animals environment. While several psychiatric medications target the LC-NE system, the possibility that its modulation during discreet developmental periods can have long-lasting consequences for mental health has not been explored. We used a pharmacogenetic strategy in mice to reversibly inhibit NE signaling during brief developmental periods to determine the long-lasting impact on adult circuits mediating emotional behavior. We also examine whether disruption of NE signaling during development results in permanent changes within the adult LC-NE system. Finally, we test whether developmental exposure to the -2 receptor agonist guanfacine recapitulates the effect seen with our pharmacogenetic strategy. Our results reveal a sensitive period (postnatal days 10-21) during which alterations in NE signaling result in long-term changes in adult emotional behavior. Changes in NE signaling during this sensitive period results in changes in stress-related LC neuron activity, alterations in -2 autoreceptor function, and circuit-specific molecular changes in LC-NE target regions in adulthood. Treating animals with guanfacine during the sensitive period produced similar results. Our findings indicate an early critical role for NE in sculpting brain circuits that support adult emotional function.

neuroscience↗