Infrared neural stimulation with 7T fMRI: A rapid in vivo method for mapping cortical connections of primate amygdala.

We have previously shown that INS-fMRI is a rapid method for mapping mesoscale brain networks in the macaque monkey brain. Focal stimulation of single cortical sites led to the activation of connected cortical locations, resulting in a global connectivity map. Here, we have extended this method for mapping brainwide networks following stimulation of single subcortical sites. As a testbed, we focused on the basal nucleus of the amygdala in the macaque monkey. We describe methods to target basal nucleus locations with submillimeter precision, pulse train stimulation methods, and statistical tests for assessing non-random nature of activations. Using these methods, we report that stimulation of precisely targeted loci in the basal nucleus produced sparse and specific activations in the brain. Activations were observed in the insular and sensory association cortices as well as activations in the cingulate cortex, consistent with known anatomical connections. What is new here is that the activations were focal and, in some cases, exhibited shifting topography with millimeter shifts in stimulation site. The precision of the method enables networks mapped from different nearby sites in the basal nucleus to be distinguished. While further investigation is needed to improve the sensitivity of this method, our analyses do support the reproducibility and non-random nature of some of the activations. We suggest that INS-fMRI is a promising method for mapping large-scale cortical and subcortical networks at high spatial resolution.

Frequency-Dependent Stimulus-Specific Adaptation and Regularity Sensitivity in the Rat Auditory Thalamus.

Recent electrophysiological studies in animals using oddball stimuli have demonstrated that neurons along the auditory pathway from the inferior colliculus to the auditory cortex (AC) have a strong response to rarely presented stimuli. This phenomenon is termed stimulus-specific adaptation (SSA), which is regarded as novelty detection. However, in the medial geniculate body (MGB), it is not clear whether SSA is frequency dependent or if neurons in the MGB are sensitive to the regularity of the stimuli. In this present study, we analyzed the relationship between stimulus frequency and SSA, as well as explored regularity sensitivity using extracellular recordings in the MGBs of rats with regular and irregular oddball stimuli. It was found MGB neurons exhibited strong SSA when the pure-tone stimulus of the oddball stimulus deviated far from the characteristic frequency, even in the ventral region of the MGB, suggesting that the MGB may contribute to SSA in the primary AC. Moreover, we found the neuronal population in the MGB was sensitive to high-order sound structure, where deviant responses were smaller and standard responses were stronger for irregular oddball stimuli. We conclude that regularity detection occurs in the MGB, but in a manner distinct from the AC.

Prenatal maternal stress induces visceral hypersensitivity of adult rat offspring through activation of cystathionine-ß-synthase signaling in primary sensory neurons.

Irritable bowel syndrome is a disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that stressors presented during gestational periods could have long-term effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of the present study is to determine whether prenatal maternal stressis a adverse factor affecting gastrointestinal sensitivity and to investigate possible mechanisms underlying prenatal maternal stress-induced visceral hypersensitivity in adult offspring. Prenatal maternal stress was induced in pregnant Sprague-Dawley rats by exposure to heterotypic intermitent stress from gestational day 7 to delivery. Prenatal maternal stress significantly increased visceromotor response to colorectal distention in adult offspring from the age of 6 weeks to 10 weeks. Prenatal maternal stress also enhanced neuronal excitability including depolarization of resting membrane potentials, reduction in rheobase, and an increase in the number of action potentials evoked by 2× and 3× rheobase current stimultion of colon-specific dorsal root ganglion neurons. Prenatal maternal stress remarkably enhanced expression of cystathionine-ß-synthase and Nav1.7 in T13-L2 thoracolumbar dorsal root ganglions both at protein and mRNA levels. Intraperitoneal injection of aminooxyacetic acid, an inhibitor of cystathionine-ß-synthase, attenuated prenatal maternal stress-induced visceral hypersensitivity in a dose-dependent manner. A consecutive seven-day administration of aminooxyacetic acid reversed the hyperexcitability of colon-specific dorsal root ganglion neurons and markedly reduced Nav1.7 expression. These results indicate that the presence of multiple psychophysical stressors during pregnancy is associated with visceral hypersensitivity in offspring, which is likely mediated by an upregualtion of cystathionine-ß-synthase and Nav1.7 expression. Prenatal maternal stress might be a significant contributor to irritable bowel syndrome, and cystathionine-ß-synthase might be a potential target for treatment for chronic visceral hypersensitivity in patients with irritable bowel syndrome.

Adrenergic ß2-receptors mediates visceral hypersensitivity induced by heterotypic intermittent stress in rats.

Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of ß2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a ß-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific ß-adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by ß2 adrenoceptor antagonist but not by ß1- or ß3-adrenoceptor antagonist. Administration of a selective ß2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of ß-adrenoceptor antagonist suppressed sustained potassium current density (IK) without any alteration of fast-inactivating potassium current density (IA). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by ß2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of ß2-adrenoceptor in DRGs and the muscularis externa of the colon. The present study might provide a potential molecular target for therapy of visceral hypersensitivity in patents with IBS.