Investigating the optimal stimulus to evoke the binaural interaction component of the auditory brainstem response.

Objective assessment of spatial and binaural hearing deficits remains a major clinical challenge. The binaural interaction component (BIC) of the auditory brainstem response (ABR) holds promise as a non-invasive biomarker for diagnosing such deficits. However, while comparative studies have reported robust BIC in animal models, BIC in humans can sometimes be unreliably evoked even in subjects with normal hearing. Here we explore the hypothesis that the standard methodology for collecting monaural ABRs may not be ideal for electrophysiological assessment of binaural hearing. This study aims to improve ABR BIC measurements by determining more optimal stimuli to evoke it. Building on previous methodology demonstrated to enhance peak amplitude of monaural ABRs, we constructed a series of level-dependent chirp stimuli based on empirically derived latencies of monaural-evoked ABR waves I, IV and the binaural-evoked BIC DN1, the most prominent BIC peak, in a cohort of ten chinchillas. We hypothesized that chirps designed based on BIC DN1 latency would specifically enhance across-frequency temporal synchrony in the afferent inputs leading to the binaural circuits that produce the BIC and would thus produce a larger DN1 than either traditional clicks or chirps designed to optimize monaural ABRs. Compared to clicks, we found that level-specific chirp stimuli evoked significantly greater BIC DN1 amplitudes, and that this effect persisted across all stimulation levels tested. However, we found no significant differences between BICs resulting from chirps created using binaural-evoked BIC DN1 latencies and those using monaural-evoked ABR waves I or IV. These data indicate that existing level-specific, monaural-based chirp stimuli may improve BIC detectability and reduce variability in human BIC measurements.

Divergent effects of acute and repeated quetiapine treatment on dopamine neuron activity in normal vs. chronic mild stress induced hypodopaminergic states.

Clinical evidence supports the use of second-generation dopamine D2 receptor antagonists (D2RAs) as adjunctive therapy or in some cases monotherapy in patients with depression. However, the mechanism for the clinical antidepressant effect of D2RAs remains unclear. Specifically, given accumulating evidence for decreased ventral tegmental area (VTA) dopamine system function in depression, an antidepressant effect of a medication that is expected to further reduce dopamine system activity seems paradoxical. In the present paper we used electrophysiological single unit recordings of identified VTA dopamine neurons to characterize the impact of acute and repeated administration of the D2RA quetiapine at antidepressant doses in non-stressed rats and those exposed to the chronic mild stress (CMS) rodent depression model, the latter modeling the hypodopaminergic state observed in patients with depression. We found that acute quetiapine increased dopamine neuron population activity in non-stressed rats, but not in CMS-exposed rats. Conversely, repeated quetiapine increased VTA dopamine neuron population activity to normal levels in CMS-exposed rats, but had no persisting effects in non-stressed rats. These data suggest that D2RAs may exert their antidepressant actions via differential effects on the dopamine system in a normal vs. hypoactive state. This explanation is supported by prior studies showing that D2RAs differentially impact the dopamine system in animal models of schizophrenia and normal rats; the present results extend this phenomenon to an animal model of depression. These data highlight the importance of studying medications in the context of animal models of psychiatric disorders as well as normal conditions.

Involvement of Infralimbic Prefrontal Cortex but not Lateral Habenula in Dopamine Attenuation After Chronic Mild Stress.

Emerging evidence supports a role for dopamine in major depressive disorder (MDD). We recently reported fewer spontaneously active ventral tegmental area (VTA) dopamine neurons (ie, reduced dopamine neuron population activity) in the chronic mild stress (CMS) rodent model of MDD. In this study, we examined the role of two brain regions that have been implicated in MDD in humans, the infralimbic prefrontal cortex (ILPFC)-that is, rodent homolog of Brodmann area 25 (BA25), and the lateral habenula (LHb) in the CMS-induced attenuation of dopamine neuron activity. The impact of activating the ILPFC or LHb was evaluated using single-unit extracellular recordings of identified VTA dopamine neurons. The involvement of each region in dopamine neuron attenuation following 5-7 weeks of CMS was then evaluated by selective inactivation. Activation of either ILPFC or LHb in normal rats potently suppressed dopamine neuron population activity, but in unique patterns. ILPFC activation selectively inhibited dopamine neurons in medial VTA, which were most impacted by CMS. Conversely, LHb activation selectively inhibited dopamine neurons in lateral VTA, which were unaffected by CMS. Moreover, only ILPFC inactivation restored dopamine neuron population activity to normal levels following CMS; LHb inactivation had no restorative effect. These data suggest that, in the CMS model of MDD, the ILPFC is the primary driver of diminished dopamine neuron responses. These findings support a neural substrate for ILPFC/BA25 linking affective and motivational circuitry dysfunction in MDD.