Objective Oxytocin is a hypothalamic neuropeptide that plays a key role in mammalian female reproductive function. Animal research indicates that central oxytocin facilitates adaptive social attachments and modulates stress and anxiety responses. Major depression is prevalent among postpubertal females, and is associated with perturbations in social attachments, dysregulation of the hypothalamic-pituitary-adrenal stress axis, and elevated levels of anxiety. Thus, depressed women may be at risk to display oxytocin dysregulation. The current study was developed to compare patterns of peripheral oxytocin release exhibited by depressed and nondepressed women. Methods Currently depressed (N = 17) and never-depressed (N = 17) women participated in a laboratory protocol designed to stimulate, measure, and compare peripheral oxytocin release in response to two tasks: an affiliation-focused Guided Imagery task and a Speech Stress task. Intermittent blood samples were drawn over the course of two, 1-hour sessions including 20-minute baseline, 10-minute task, and 30-minute recovery periods. Results The 10-minute laboratory tasks did not induce identifiable, acute changes in peripheral oxytocin. However, as compared with nondepressed controls, depressed women displayed greater variability in pulsatile oxytocin release over the course of both 1-hour sessions, and greater oxytocin concentrations during the 1-hour affiliation-focused imagery session. Oxytocin concentrations obtained during the imagery session were also associated with greater symptoms of depression, anxiety, and interpersonal dysfunction. Conclusions Depressed women are more likely than controls to display a dysregulated pattern of peripheral oxytocin release. Further research is warranted to elucidate the clinical significance of peripheral oxytocin release in both depressed and nondepressed women.

. Enhanced initial and sustained intake of sucrose solution in mice with an oxytocin gene deletion. Am J Physiol Regul Integr Comp Physiol 289: R1798 -R1806, 2005. First published September 8, 2005 doi:10.1152/ajpregu.00558.2005.-Laboratory mice drink little sucrose solution on initial exposure, but later develop a strong preference for sucrose over water that plateaus after a few days. Both the initial neophobia and later plateau of sucrose intake may involve central oxytocin (OT) signaling pathways. If so, then mice that lack the gene for OT [OT knockout (KO)] should exhibit enhanced initial and sustained sucrose intake compared with wild-type (WT) cohorts. To test this hypothesis, female OT KO and WT mice (11-13 mo old) were given a two-bottle choice between 10% sucrose and water available ad libitum for 4 days. On the first day, sucrose intake was 20-fold greater in OT KO mice compared with WT cohorts. The avid sucrose consumption by OT KO mice increased further on day 2 and was sustained at significantly higher levels than intake by WT mice. Enhanced initial and sustained sucrose intake also was observed in 5-to 7-mo-old male OT KO mice. The effect of genotype was observed over a range of sucrose concentrations and was maintained over at least 8 days of continual exposure. However, there was no effect of genotype on daily intake of sucroseenriched powdered chow. These findings indicate that the genetic absence of OT in mice is associated with enhanced initial and sustained intake of sucrose solutions. Thus central OT pathways may normally participate in limiting initial intake of novel ingesta and may also participate in limiting intake of sweet, highly palatable familiar ingesta.sugar; palatability; overeating; satiety RESULTS FROM STUDIES USING rats and mice support the view that oxytocin (OT) acts centrally to inhibit intake of food and other solutes (i.e., sodium chloride, NaCl, solution) under certain experimental conditions. For example, fasting-induced food intake is suppressed after central infusion of synthetic OT in rats (3, 27), and OT receptor blockade reduces the anorexic response to systemically administered hypertonic saline or to centrally infused corticotropin-releasing factor (26, 28, 39 -43). Similarly, dehydration anorexia is markedly attenuated in mice with an OT gene deletion [OT knockout (KO)] (36), and OT KO mice consume more NaCl solution than wild-type (WT) mice after overnight fluid deprivation (2) or after exposure to mild environmental stress (34). However, WT and OT KO mice ingest similar amounts of standard chow under ad libitum baseline conditions, after overnight food deprivation when drinking water is available, and after systemic administration of either cholecystokinin octapeptide or D-fenfluramine (18,36). These findings indicate that neurochemical systems other than OT are sufficient to limit or suppress food intake in mice under such conditions. OT neurons are activated by a variety of stressful and anxiogenic stimuli in rats (9,13,21,22,24,44,45) and mice (1,20,25)....

Cochlear sound encoding depends on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), but reliance on specific pore-forming subunits is unknown. With 5-week-old male C57BL/6J Gria3 knockout mice (i.e., subunit GluA3KO) we determined cochlear function, synapse ultrastructure and AMPAR molecular anatomy at ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons. GluA3KO and wild-type (GluA3WT) mice reared in ambient sound pressure level (SPL) of 55-75 dB had similar auditory brainstem response (ABR) thresholds, wave-1 amplitudes and latencies. Postsynaptic densities (PSDs), presynaptic ribbons, and synaptic vesicle sizes were all larger on the modiolar side of the IHCs from GluA3WT, but not GluA3KO, demonstrating GluA3 is required for modiolar-pillar synapse differentiation. Presynaptic ribbons juxtaposed with postsynaptic GluA2/4 subunits were similar in quantity, however, lone ribbons were more frequent in GluA3KO and GluA2-lacking synapses were observed only in GluA3KO. GluA2 and GluA4 immunofluorescence volumes were smaller on the pillar side than the modiolar side in GluA3KO, despite increased pillar-side PSD size. Overall, the fluorescent puncta volumes of GluA2 and GluA4 were smaller in GluA3KO than GluA3WT. However, GluA3KO contained less GluA2 and greater GluA4 immunofluorescence intensity relative to GluA3WT (3-fold greater mean GluA4:GluA2 ratio). Thus, GluA3 is essential in development, as germline disruption of Gria3 caused anatomical synapse pathology before cochlear output became symptomatic by ABR. We propose the hearing loss in older male GluA3KO mice results from progressive synaptopathy evident in 5-week-old mice as decreased abundance of GluA2 subunits and an increase in GluA2-lacking, GluA4-monomeric Ca2+-permeable AMPARs.

Cochlear outer hair cells (OHCs) are known to uniquely participate in auditory processing through their electromotility, and like inner hair cells, are also capable of releasing vesicular glutamate onto spiral ganglion (SG) neurons: in this case, onto the sparse Type II SG neurons. However, unlike glutamate signaling at the inner hair cell-Type I SG neuron synapse, which is robust across a wide spectrum of sound intensities, glutamate signaling at the OHC-Type II SG neuron synapse is weaker and has been hypothesized to occur only at intense, possibly damaging sound levels. Here, we tested the ability of the OHC-Type II SG pathway to signal to the brain in response to moderate, nondamaging sound (80 dB SPL) as well as to intense sound (115 dB SPL). First, we determined the VGluTs associated with OHC signaling and then confirmed the loss of glutamatergic synaptic transmission from OHCs to Type II SG neurons in KO mice using dendritic patch-clamp recordings. Next, we generated genetic mouse lines in which vesicular glutamate release occurs selectively from OHCs, and then assessed c-Fos expression in the cochlear nucleus in response to sound. From these analyses, we show, for the first time, that glutamatergic signaling at the OHC-Type II SG neuron synapse is capable of activating cochlear nucleus neurons, even at moderate sound levels.

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