Biology subjects

Nishimura, K. J.

Publications and source records attributed to Nishimura, K. J..

3 recordsLinked to original sources

bioRxiv2025

Paraventricular Thalamus Hyperactivity Mediates Stress-Induced Sensitization of Unlearned Fear but Not Stress-Enhanced Fear Learning (SEFL)

Exposure to stress can cause long-lasting enhancement of fear and other defensive responses that extend beyond the cues or contexts associated with the original traumatic event. These nonassociative consequences of stress, referred to as fear sensitization, are thought to underlie some symptoms of trauma-related disorders. Fear sensitization has been predominately studied using the Stress-Enhanced Fear Learning (SEFL) paradigm, which models the stress-induced amplification of fear learning. Less is known about the mechanisms through which unlearned fear responses are sensitized by stress. Here, we investigated the neural mechanisms for sensitization of unlearned fear responses using a paradigm we termed Stress-Enhanced Fear Responding (SEFR). In this model, mice exposed to a single session of footshock stress exhibit enhanced freezing to a novel tone stimulus. To investigate brain regions that might mediate SEFR, we first used c-Fos mapping to identify neural activity changes associated with stress-induced enhancement of unlearned fear. Our c-Fos screen identified the posterior paraventricular thalamus (pPVT) as a region that was persistently hyperactive after footshock stress and whose activity correlated with behavioral expression of SEFR. Using fiber photometry, we observed that SEFR, but not SEFL, was associated with increased activity in the pPVT. Next, we found that chemogenetic inhibition of the pPVT blocked both the induction of SEFR during stress and its later expression, while artificial stimulation of pPVT in stress-naive mice was sufficient to recapitulate SEFR. Interestingly, pPVT inhibition or stimulation did not affect acquisition or expression of SEFL. In conclusion, our results indicate that sensitization of fear learning (SEFL) and sensitization of unlearned fear (SEFR) have distinct neural mechanisms. Our results identify pPVT hyperactivity as a mechanism for stress-induced sensitization of unlearned fear and highlight pPVT as a potential target for treating arousal and reactivity symptoms of trauma- and stressor-related disorders.

neuroscience↗

bioRxiv2022

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. While Erk1/2 inactivation does not alter CIN number, we discovered a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of CINs. ERK1/2 signaling is also necessary for chemogenetic activity-dependent FOSB expression in CINs in vivo. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression in Erk1/2 mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.

neuroscience↗

bioRxiv2019

Hyperactive MEK1 signaling in cortical GABAergic interneurons causes embryonic parvalbumin-neuron death and deficits in behavioral inhibition

Abnormal ERK/MAPK pathway activity is an important contributor to the neuropathogenesis of many disorders including Fragile X, Rett, 16p11.2 Syndromes, and the RASopathies. Individuals with these syndromes often present with intellectual disability, ADHD, autism, and epilepsy. However, the pathological mechanisms that underly these deficits are not fully understood. Here, we examined whether hyperactivation of MEK1 signaling modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallium. Adult mutants displayed a significant loss of mature parvalbumin-expressing (PV) CINs, but not somatostatin-expressing CINs, during postnatal development and a modest reduction in perisomatic inhibitory synapse formation on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype and minor differences in intrinsic electrophysiological properties. These changes coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity in the developing brain. Indeed, we found that mutants exhibit a significant impairment in the acquisition of a behavioral test that relies on behavioral response inhibition, a process linked to ADHD-like phenotypes. Overall, our data suggests PV-CIN development is particularly sensitive to hyperactive MEK1 signaling which may underlie neurological deficits frequently observed in ERK/MAPK-linked syndromes.\n\nSignificance StatementThe RASopathies are a family of neurodevelopmental syndromes caused by mutations that lead to increased RAS/RAF/MEK/ERK signaling and are associated with intellectual disability, epilepsy, and ADHD. We do not fully understand how distinct neuronal subtypes are affected in these syndromes. Here, we show that increased MEK signaling in developing mice promotes the embryonic death of a specific subset of cortical inhibitory neurons that express parvalbumin. Surviving mutant parvalbumin neurons also show significant changes in crucial maturation processes, which coincide with increased seizure susceptibility and profound deficits in behavioral inhibition. These data suggest that deficits in inhibitory circuit development contribute to RASopathy neuropathogenesis and indicate that therapeutic strategies targeting inhibitory interneuron dysfunction may be beneficial for these individuals.

neuroscience↗