Phase-adaptive brain stimulation of striatal D1 medium spiny neurons in dopamine-depleted mice

Abstract

Brain rhythms are strongly linked with behavior, and abnormal rhythms can signify pathophysiology. For instance, the basal ganglia exhibit a wide range of low-frequency oscillations during movement, but pathological “beta” rhythms at ~ 20 Hz have been observed in Parkinson’s disease (PD) and in PD animal models. All brain rhythms have a frequency, which describes how often they oscillate, and a phase, which describes the precise time that peaks and troughs of brain rhythms occur. Although frequency has been extensively studied, the relevance of phase is unknown, in part because it is difficult to causally manipulate the instantaneous phase of ongoing brain rhythms. Here, we developed a phase-adaptive, real-time, closed-loop algorithm to deliver optogenetic stimulation at a specific phase with millisecond latency. We combined this Phase-Adaptive Brain STimulation (PABST) approach with cell-type-specific optogenetic methods to stimulate basal ganglia networks in dopamine-depleted mice that model motor aspects of human PD. We focused on striatal medium spiny neurons expressing D1-type dopamine receptors because these neurons can facilitate movement. We report three main results. First, we found that our approach delivered PABST within system latencies of 13 ms. Second, we report that closed-loop stimulation powerfully influenced the spike-field coherence of local brain rhythms within the dorsal striatum. Finally, we found that both 4 Hz PABST and 20 Hz PABST improved movement speed, but we found differences between phase only with 4 Hz PABST. These data provide causal evidence that phase is relevant for brain stimulation, which will allow for more precise, targeted, and individualized brain stimulation. Our findings are applicable to a broad range of preclinical brain stimulation approaches and could also inform circuit-specific neuromodulation treatments for human brain disease.

Unraveling Sex Differences in Affect Processing: Unique Oscillatory Signaling Dynamics in the Infralimbic Cortex and Nucleus Accumbens Shell

“…In closing, the current study revealed unique oscillatory signaling dynamics in the IL-NAcSh circuit during innate versus learned negative affect that differed in male and female rats. While our previous optogenetic work implicated a role of this circuit in learned negative affect only in male rats ( 31 ), future studies using other techniques such as closed-loop signal processing and optogenetics are needed to determine whether the specific oscillatory signaling properties that were observed here are indeed causally linked to innate and/or learned negative affect ( 45 , 46 , 47 , 48 , 49 ). Nevertheless, our findings clearly show that while innate and learned affective behaviors do not differ across sex, signaling dynamics in the IL-NAcSh are not engaged in the same manner in male and female rats.…”

Generation and validation of a D1 dopamine receptor Flpo knock-in mouse

“…Transgenic mice have been a valuable tool for understanding the D1DR+ population in various brain circuits and areas (Lemberger et al, 2007). Previously, our group has used D1-Cre mice to modulate local cortical and striatal networks, which has the potential to improve both cognition and movement (Kim et al, 2017(Kim et al, , 2022Kim and Narayanan, 2019). Although D1DR+ neurons expressing Cre recombinase are a powerful tool, D1-Cre mice are derived from BAC-transgenic lines and thus, can have insertion position effect that can exhibit variability in transgene expression.…”

Complementary cognitive roles for D2-MSNs and D1-MSNs during interval timing

“…Future stimulation approaches carefully titrated to striatal physiology may influence interval timing without affecting movement 48 .…”