Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT₆ receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister-hooded rats (weaned on post-natal day 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a two week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms

ICAR: endoscopic skull‐base surgery

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Neural Masking by Sub-threshold Electric Stimuli: Animal and Computer Model Results

Electric stimuli can prosthetically excite auditory nerve fibers to partially restore sensory function to individuals impaired by profound or severe hearing loss. While basic response properties of electrically stimulated auditory nerve fibers (ANF) are known, responses to complex, time-changing stimuli used clinically are inadequately understood. We report that forward-masker pulse trains can enhance and reduce ANF responsiveness to subsequent stimuli and the novel observation that sub-threshold (nonspike-evoking) electric trains can reduce responsiveness to subsequent pulse-train stimuli. The effect is observed in the responses of cat ANFs and shown by a computational biophysical ANF model that simulates rate adaptation through integration of external potassium cation (K) channels. Both low-threshold (i.e., Klt) and high-threshold (Kht) channels were simulated at each node of Ranvier. Model versions without Klt channels did not produce the sub-threshold effect. These results suggest that some such accumulation mechanism, along with Klt channels, may underlie sub-threshold masking observed in cat ANF responses. As multichannel auditory prostheses typically present sub-threshold stimuli to various ANF subsets, there is clear relevance of these findings to clinical situations