Maximizing translational value in models of compulsive behavior: A commentary on Pickenhan et al. (2024).

In this issue of Cognitive, Affective, and Behavioral Neuroscience, Pickenhan et al. (2024) discuss the need for translational studies to understand features underlying obsessive-compulsive disorder (OCD). They highlight the translational value of the observing-response task (ORT) for modeling functional and maladaptive checking behaviors, a common symptom of OCD.

Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder.

Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation.

Assembly of presynaptic active zones from cytoplasmic transport packets.

Little is known about presynaptic assembly during central nervous system synaptogenesis. Here we used time-lapse fluorescence imaging, immunocytochemistry and electron microscopy to study hippocampal neuronal cultures transfected with a fusion construct of the presynaptic vesicle protein VAMP and green fluorescent protein. Our results suggest that major cytoplasmic and membrane-associated protein precursors of the presynaptic active zone are transported along developing axons together as discrete packets. Retrospective electron microscopy demonstrated varied vesicular and tubulovesicular membrane structures. Packets containing these heterogeneous structures were stabilized specifically at new sites of dendrite- and axon-initiated cell-cell contact; within less than one hour, evoked vesicle recycling was observed at these putative nascent synapses. These observations suggest that substantial membrane remodeling may be necessary to produce the uniform vesicles typical of the mature active zone, and that many presynaptic proteins may be united early in their biogenesis and sorting pathways.

Estriol: a potent regulator of TNF and IL-6 expression in a murine model of endotoxemia.

The increased incidence of autoimmune disease in premenopausal women suggests the involvement of sex steroids in the pathogenesis of these disease processes. The effects of estrogen on autoimmunity and inflammation may involve changes in the secretion of inflammatory mediators by mononuclear phagocytes. Estradiol, for example, has been reported to regulate TNF, IL-6, IL-1 and JE expression. In the present study the effects of the estrogen agonist, estriol, on cytokine expression have been investigated in mice administered a sublethal lipopolysaccharide, LPS, challenge. Pretreatment of mice with pharmacologic doses of estriol, 0.4-2 mg/kg, resulted in a significant increase in serum TNF levels in both control and autoimmune MRL/lpr mice, following LPS challenge. This increase in TNF over the placebo group was blocked by the estrogen antagonist tamoxifen. Estriol treated mice also exhibited a rapid elevation in serum IL-6 levels following LPS challenge with the peak increase occurring 1 hr post LPS. This contrasted with the placebo group in which maximal serum IL-6 levels were detected at 3 hrs post challenge. This shift in the kinetics of IL-6 increase by estriol was inhibited by tamoxifen. The estriol mediated effects of TNF and IL-6 serum levels were consistent with the changes in TNF and IL-6 mRNA observed ex vivo in elicited peritoneal macrophages. Macrophage cultures from estriol treated animals however, did not demonstrate significant differences from the placebo group for TNF or NO secretion following in vitro LPS challenge. These results suggest that the estrogen agonist estriol can have significant quantitative, TNF, and kinetic, IL-6, effects on inflammatory monokines produced in response to an endotoxin challenge.