Biology subjects

Spitzer, N. C.

Publications and source records attributed to Spitzer, N. C..

5 recordsLinked to original sources

bioRxiv2023

Generalized fear following acute stress is caused by change in co-transmitter identity of serotonergic neurons

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. Here we show that generalized fear in mice in response to footshock results from a transmitter switch from glutamate to GABA in serotonergic neurons of the lateral wings of the dorsal raphe. We observe a similar change in transmitter identity in the postmortem brains of PTSD patients. Overriding the transmitter switch in mice using viral tools prevents the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors trigger the switch, and prompt antidepressant treatment blocks the co-transmitter switch and generalized fear. Our results provide new understanding of the plasticity involved in fear generalization. One sentence summaryAcute stress produces generalized fear by causing serotonergic neurons to switch their co-transmitter from glutamate to GABA

neuroscience↗

bioRxiv2022

Postsynaptic receptors regulate presynaptic neurotransmitter stability

Stable matching of neurotransmitters with their receptors is fundamental to synapse function, to achieve reliable and robust communication in neural circuits. Presynaptic neurotransmitters regulate selection of postsynaptic transmitter receptors. However, whether postsynaptic receptors regulate selection of presynaptic transmitters is unknown. Here we show that blockade of postsynaptic acetylcholine receptors at the neuromuscular junction leads to loss of the cholinergic phenotype in motor neurons and stabilization of an earlier, developmentally transient glutamatergic phenotype. Exogenous postsynaptic expression of GABAA receptors leads to the stabilization of an earlier, developmentally transient GABAergic motor neuron phenotype. Both acetylcholine receptors and GABA receptors are linked to presynaptic neurons through trans-synaptic bridges. Knock-down of different components of these trans-synaptic bridges prevents stabilization of the cholinergic and GABAergic phenotypes. We conclude that this bidirectional communication enforces a match between transmitter and receptor and ensures the fidelity of synaptic transmission. Our findings suggest a role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.

neuroscience↗

bioRxiv2022

Phencyclidine and methamphetamine cause cognitive deficits by changing pyramidal neuron transmitter identity in the prefrontal cortex

Cognitive deficits are a long-lasting consequence of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, impair memory by causing the same glutamatergic neurons in the medial prefrontal cortex to gain a GABAergic phenotype and decrease their expression of the vesicular glutamate transporter. Suppressing drug-induced gain of GABA with RNA-interference prevents the appearance of memory deficits. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Normalizing the activity of prefrontal glutamatergic neurons after drug-exposure reverses the gain of GABAergic phenotype and rescues the associated memory deficits. Increased activity of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce the change in transmitter identity. The results reveal a shared and reversible mechanism by which exposure to different drugs causes cognitive deficits.

neuroscience↗

bioRxiv2019

Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain

Physical exercise promotes motor skill learning in normal individuals and those with neurological disorders but its mechanism of action is unclear. We found that one week of voluntary wheel running enhances the acquisition of motor skills in adult mice. One week of running also induces switching from ACh to GABA expression in neurons in the caudal pedunculopontine nucleus (cPPN). The switching neurons make projections to the substantia nigra (SN), ventral tegmental area (VTA) and ventrolateral-ventromedial nuclei of the thalamus (VL-VM), which regulate acquisition of motor skills. Use of viral vectors to override transmitter switching blocks the beneficial effect of running on motor skill learning. We suggest that neurotransmitter switching provides the basis by which sustained running benefits motor skill learning, presenting a new target for clinical treatment of movement disorders.

neuroscience↗

bioRxiv2019

Photoperiod-induced neurotransmitter plasticity declines with aging: an epigenetic regulation?

Neuroplasticity has classically been understood to arise through changes in synaptic strength or synaptic connectivity. A newly discovered form of neuroplasticity, neurotransmitter switching, involves changes in neurotransmitter identity. Chronic exposure to different photoperiods alters the number of dopamine (tyrosine hydroxylase, TH+) and somatostatin (SST+) neurons in the paraventricular nucleus (PaVN) of the hypothalamus of adult rats and results in discrete behavioral changes. Here we investigate whether photoperiod-induced neurotransmitter switching persists during aging and whether epigenetic mechanisms of histone acetylation and DNA methylation may contribute to this neurotransmitter plasticity. We show that this plasticity is robust at 1 and at 3 months but reduced in TH+ neurons at 12 months and completely abolished in both TH+ and SST+ neurons by 18 months. De novo methylation and histone 3 acetylation were observed following short-day photoperiod exposure in both TH+ and SST+ neurons at 1 and 3 months while an overall increase in methylation of SST+ neurons paralleled neuroplasticity reduction at 12 and 18 months. Histone acetylation increased in TH+ neurons and decreased in SST+ neurons following short-day exposure at 3 months while the total number of acetylated PaVN neurons remained constant. Reciprocal histone acetylation in TH+ and SST+ neurons suggests the importance of studying epigenetic regulation at the circuit level for identified cell phenotypes. The association of age-dependent reduction in neurotransmitter plasticity and changes in DNA methylation and acetylation patterns in two neuronal phenotypes known to switch transmitter identity suggests mechanistic insights into transmitter plasticity in the aging brain. SIGNIFICANCENeurotransmitter switching, like changes in synaptic strength, formation of new synapses and synapse remodeling, declines with age. This age-dependent reduction in transmitter plasticity is associated with changes in levels of DNA methylase and histone deacetylase that imply epigenetic regulation of transcription. A reciprocal pattern of histone acetylation in a single population of neurons that depends on the transmitter expressed emphasizes the value of studying epigenetic mechanisms at the level of cell phenotypes rather than cell genotypes or whole tissue. The findings may be useful for developing approaches for non-invasive treatment of disorders characterized by neurotransmitter dysfunction.

neuroscience↗