Neuroscience
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Individual differences in human temperament can increase the risk of psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats. ⋯ We found that HR rats display higher COX activity in the amygdala and specific hippocampal subregions compared to LRs during the first 2 weeks of life. Correlational analysis examining COX levels across several brain regions and multiple early postnatal time points suggested desynchronization in the developmental timeline of the limbic HR versus LR brain during the first two postnatal weeks. These early divergent COX activity levels may reflect altered circuitry or synaptic activity in the early postnatal HR/LR brain, which could contribute to the emergence of their distinct behavioral phenotypes.
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As disturbance in auditory steady-state response (ASSR) has been consistently found in many neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, there is considerable interest in the development of translational rat models to elucidate the underlying neural and neurochemical mechanisms involved in ASSR. This is the first study to investigate the effects of the non-selective muscarinic antagonist scopolamine and the cholinesterase inhibitor donepezil (also in combination with scopolamine) on ASSR. We recorded the local field potentials through the chronic microelectrodes implanted in the auditory cortex of freely moving rat. ⋯ Donepezil augmented 40-Hz steady-state power and phase-locking. Scopolamine combined with donepezil had an enhanced effect on the phase-locking, but not power of ASSR. These changes induced by cholinergic drugs suggest an involvement of muscarinic neurotransmission in auditory processing and provide a rodent model investigating the neurochemical mechanism of neurophysiological deficits seen in patients.
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We propose that the extracellular matrix (ECM) signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation in the rat hind paw. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by pretreatment with HMWH or A5G27. ⋯ Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the ECM that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.
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Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions characterized by difficulties in communication and social interactions, restricted, repetitive behaviors and sensory abnormalities. Notably, the vast majority of individuals with ASD experience some degree of auditory dysfunction and we have recently reported consistent hypoplasia and dysmorphology in auditory brainstem centers in individuals with ASD. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of ASD. ⋯ Additionally, we observed a larger dispersion of c-Fos-positive neurons and shifted tonotopic bands in VPA-exposed rats. We interpret these findings to suggest hyper-responsiveness to sounds and disrupted mapping of sound frequencies after prenatal VPA exposure. Based on these findings, we suggest that such abnormal patterns of activation may play a role in auditory processing deficits in ASD.
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Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. ⋯ It also significantly inhibited the TRPA1, but not the TRPV1 activation-induced CGRP release from the peripheral sensory nerve endings in a concentration-dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons.