Distinct Alteration Patterns of Resting-State Functional Connectivity of the Corticostriatal Circuits Effected by Cigarette Smoking in Mild Cognitive Impairment Patients and Cognitively Normal subjects

To explore the interaction effects of smoking status (non-smoking vs. smoking) and disease (cognitively normal (CN) vs. MCI) based on resting-state functional connectivity (rsFC) of the corticostriatal circuits. We included 304 CN non-smokers, 44 CN smokers, 130 MCI non-smokers, and 33 MCI smokers. The seed-based rsFC of striatal subregions (caudate, putamen, and nucleus accumbens [NAc]) with the whole-brain voxel was calculated. Furthermore, we performed mixed effect analysis to explore the interaction effects between smoking status and disease. Significant interaction effects were detected between: (1) right caudate and left inferior parietal lobule (IPL); (2) right putamen and bilateral cuneus; (3) bilateral NAc and bilateral anterior cingulate cortex (ACC). The post-hoc analyses revealed that the CN smokers showed increased rsFC between right caudate and left IPL compared to non-smokers; while the MCI smokers demonstrated decreased rsFC between right putamen and cuneus, and increased rsFC between bilateral NAc and ACC compared to non-smokers. In MCI smokers, the rsFC value between left NAc and ACC was positively correlated with Semantic Verbal Fluency (SVF, r = 0.387, p = 0.026), and the rsFC value between right NAc and ACC was positively correlated with SVF (r = 0.390, p = 0.025), Wechsler memory scale-logical memory (WMS-LM) immediate recall (r = 0.378, p = 0.03), and WMS-LM delayed recall (r = 0.367, p = 0.036). Our findings suggest that chronic nicotine exposure may lead to functional connectivity alterations of corticostriatal circuits in MCI patients, and the pattern is different from CN smokers.

Mice are not automatons; subjective experience in premotor circuits guides behavior

Subjective experience is a powerful driver of decision-making and continuously accrues. However, most neurobiological studies constrain analyses to task-related variables and ignore how continuously and individually experienced internal, temporal, and contextual factors influence adaptive behavior during decision-making and the associated neural mechanisms. We show mice rely on learned information about recent and longer-term subjective experience of variables above and beyond prior actions and reward, including checking behavior and the passage of time, to guide self-initiated, self-paced, and self-generated actions. These experiential variables were represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrated this information to bias strategy-level decision-making, and DMS projections used specific aspects of this recent experience to plan upcoming actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.

Connectivity profile laterality in corticostriatal functional circuitry: a fingerprinting approach

An abnormal magnitude of hemispheric difference (i.e. laterality) in corticostriatal circuits is a shared feature of numerous neurodevelopmental and psychiatric disorders. Detailed quantitation and regional localization of corticostriatal laterality in normative samples stands to further the understanding of hemispheric differences in healthy and disease states. Here, we used a fingerprinting approach to quantify functional connectivity profile laterality (the overall magnitude by which a voxel's profile of connectivity with homotopic regions of the ipsilateral and contralateral cortex differs) in the striatum. Laterality magnitude heatmaps revealed laterality hotspots (constituting outliers in the voxelwise distribution) in the right ventrolateral putamen and left central caudate. Findings were replicated in an independent sample, with significant (p<0.05) spatial overlap observed between the location of the laterality hotspots across samples, as measured via Dice coefficients. At both hotspots, a primary driver of overall laterality was the difference in striatal connectivity strength with the right and left pars opercularis of the inferior frontal gyrus. Right and left striatum laterality magnitude maps were found to significantly differ (p<0.05) at the hotspot locations. Moreover, using subjects' left, but not right, striatum laterality magnitude maps, a support vector machine trained on a discovery sample (n=77) and tested on a replication sample (n=77) significantly predicted (r=0.25, p=0.028) subject performance on a language task, known for its lateralized nature. Laterality magnitude maps remained consistent across different cortical atlas parcellations and did not differ significantly between right handed and left handed individuals. In sum, meaningful variation in functional connectivity profile laterality, both spatially within the striatum and across subjects, is evident in corticostriatal circuits. Findings provide a basis to examine corticostriatal connectivity profile laterality in psychiatric illness.

Temporal learning among prefrontal and striatal ensembles

Behavioral flexibility requires the prefrontal cortex and striatum. Here, we investigate neuronal ensembles in the medial frontal cortex (MFC) and the dorsomedial striatum (DMS) during one form of behavioral flexibility: learning a new temporal interval. We studied corticostriatal neuronal activity as rodents trained to respond after a 12-second fixed interval (FI12) learned to respond at a shorter 3-second fixed interval (FI3). On FI12 trials, we discovered time-related ramping was reduced in the MFC but not in the DMS in two-interval vs. one-interval sessions. We also found that more DMS neurons than MFC neurons exhibited differential interval-related activity on the first day of two-interval performance. Finally, MFC and DMS ramping was similar with successive days of two-interval performance but DMS temporal decoding increased on FI3 trials. These data suggest that the MFC and DMS play distinct roles during temporal learning and provide insight into corticostriatal circuits.

Dissociable roles of central striatum and anterior lateral motor area in initiating and sustaining naturalistic behavior

Although much is known about how corticostriatal circuits mediate behavioral selection, most previous work has been conducted in highly trained animals engaged in instrumental tasks. Understanding how corticostriatal circuits mediate behavioral selection and initiation in a naturalistic setting is critical to understanding how the brain chooses and executes behavior in unconstrained situations. Central striatum (CS), an understudied region that lies in the middle of the motor-limbic topography, is well-poised to play an important role in these processes since its main cortical inputs (Corbit et al., 2019) have been implicated in behavioral flexibility (lateral orbitofrontal cortex (Kim and Ragozzino, 2005)) and response preparation (anterior lateral motor area, ALM) (Li et al., 2015), However, although CS activity has been associated with conditioned grooming behavior in transgenic mice (Burguiere et al., 2013), the role of CS and its cortical inputs in the selection of spontaneous behaviors has not been explored. We therefore studied the role of CS corticostriatal circuits in behavioral selection in an open field context.Surprisingly, using fiber photometry in this unconstrained environment, we found that population calcium activity in CS was specifically increased at onset of grooming, and not at onset of other spontaneous behaviors such as rearing or locomotion. Supporting a potential selective role for CS in the initiation of grooming, bilateral optogenetic stimulation of CS evoked immediate onset grooming-related movements. However, these movements resembled subcomponents of grooming behavior and not full-fledged grooming bouts, suggesting that additional input(s) are required to appropriately sequence and sustain this complex motor behavior once initiated. Consistent with this idea, optogenetic stimulation of CS inputs from ALM generated sustained grooming responses that evolved on a time-course paralleling CS activation monitored using single-cell calcium imaging. Furthermore, fiber photometry in ALM demonstrated a gradual ramp in calcium activity that peaked at time of grooming termination, supporting a potential role for ALM in encoding length of this spontaneous sequenced behavior. Finally, dual color dual region fiber photometry indicated that CS activation precedes ALM during naturalistic grooming sequences. Taken together, these data support a novel model in which CS activity is sufficient to initiate grooming behavior, but ALM activity is necessary to sustain and encode the length of grooming bouts. Thus, the use of an unconstrained behavioral paradigm has allowed us to uncover surprising roles for CS and ALM in the initiation and maintenance of spontaneous sequenced behaviors.

Temporal Learning Among Prefrontal and Striatal Ensembles

Behavioral flexibility requires the prefrontal cortex and striatum, but it is unclear if these structures play similar or distinct roles in adapting to novel circumstances. Here, we investigate neuronal ensembles in the medial frontal cortex (MFC) and the dorsomedial striatum (DMS) during one form of behavioral flexibility: learning a new temporal interval. We studied corticostriatal neuronal activity as rodents trained to respond after a 12-s fixed interval (FI12) learned to respond at a shorter 3-s fixed interval (FI3). On FI12 trials, we found that a key form of temporal processing—time-related ramping activity—decreased in the MFC but did not change in the DMS as animals learned to respond at a shorter interval. However, while MFC and DMS ramping was stable with successive days of two-interval performance, temporal decoding by DMS ensembles improved on FI3 trials. Finally, when comparing FI12 versus FI3 trials, we found that more DMS neurons than MFC neurons exhibited differential interval-related activity early in two-interval performance. These data suggest that the MFC and DMS play distinct roles during temporal learning and provide insight into corticostriatal circuits.