BACKGROUND AND PURPOSEThe D1CT-7 mouse is one of the best known animal models of Tourette syndrome (TS), featuring spontaneous tic-like behaviours sensitive to standard TS therapies; these characteristics ensure a high face and predictive validity of this model, yet its construct validity remains elusive. To address this issue, we studied the responses of D1CT-7 mice to two critical components of TS pathophysiology: the exacerbation of tic-like behaviours in response to stress and the presence of sensorimotor gating deficits, which are thought to reflect the perceptual alterations causing the tics. EXPERIMENTAL APPROACHD1CT-7 and wild-type (WT) littermates were subjected to a 20 min session of spatial confinement (SC) within an inescapable, 10 cm wide cylindrical enclosure. Changes in plasma corticosterone levels, tic-like behaviours and other spontaneous responses were measured. SC-exposed mice were also tested for the prepulse inhibition (PPI) of the startle response (a sensorimotor gating index) and other TS-related behaviours, including open-field locomotion, novel object exploration and social interaction and compared with non-confined counterparts. KEY RESULTSSC produced a marked increase in corticosterone concentrations in both D1CT-7 and WT mice. In D1CT-7, but not WT mice, SC exacerbated tic-like and digging behaviours, and triggered PPI deficits and aggressive responses. Conversely, SC did not modify locomotor activity or novel object exploration in D1CT-7 mice. Both tic-like behaviours and PPI impairments in SC-exposed D1CT-7 mice were inhibited by standard TS therapies and D1 dopamine receptor antagonism. CONCLUSIONS AND IMPLICATIONSThese findings collectively support the translational and construct validity of D1CT-7 mice with respect to TS. AbbreviationsNC, non-confined; PPI, prepulse inhibition of the acoustic startle reflex; SC, spatial confinement; TS, Tourette syndrome

Neural recording systems that interface with implanted microelectrodes are used extensively in experimental neuroscience and neural engineering research. Interface electronics that are needed to amplify, filter, and digitize signals from multichannel electrode arrays are a critical bottleneck to scaling such systems. This paper presents the design and testing of an electronic architecture for intracortical neural recording that drastically reduces the size per channel by rapidly multiplexing many electrodes to a single circuit. The architecture utilizes mixed-signal feedback to cancel electrode offsets, windowed integration sampling to reduce aliased high-frequency noise, and a successive approximation analog-to-digital converter with small capacitance and asynchronous control. Results are presented from a 180 nm CMOS integrated circuit prototype verified using in vivo experiments with a tungsten microwire array implanted in rodent cortex. The integrated circuit prototype achieves <0.004 mm2 area per channel, 7 µW power dissipation per channel, 5.6 µVrms input referred noise, 50 dB common mode rejection ratio, and generates 9-bit samples at 30 kHz per channel by multiplexing at 600 kHz. General considerations are discussed for rapid time domain multiplexing of high-impedance microelectrodes. Overall, this work describes a promising path forward for scaling neural recording systems to numbers of electrodes that are orders of magnitude larger.

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen

Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson’s disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at doses (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with monoamine-depleting agent reserpine (RES), at low doses (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.