Subregions Of Prefrontal Cortex Research Articles

A calculus of probability or belief? Neural underpinnings of social decision-making in a card game

For decades, the prefrontal cortex (PFC) has been the focus of social neuroscience research, specifically regarding its role in competitive social decision-making. However, the distinct contributions of PFC subregions when making strategic decisions involving multiple types of information (social, non-social, and mixed information) remain unclear. This study investigates decision-making strategies (pure probability calculation vs. mentalizing) and their neural representations using functional near-infrared spectroscopy (fNIRS) data collected during a two-person card game. We observed individual differences in information processing strategy, indicating that some participants relied more on probability than others. Overall, the use of pure probability decreased over time in favor of other types of information (e.g., mixed information), with this effect being more pronounced within-round trials than across rounds. In the brain, (1) the lateral PFC activates when decisions are driven by probability calculations; (2) the right lateral PFC responds to trial difficulty; and (3) the anterior medial PFC is engaged when decision-making involves mentalizing. Furthermore, neural synchrony, which reflects the real-time interplay between individuals' cognitive processes, did not consistently contribute to correct decisions and fluctuated throughout the experiment, suggesting a hierarchical mentalizing mechanism at work.

Change in activity patterns in the prefrontal cortex in different phases during the dual-task walking in older adults

BackgroundStudies using functional near-infrared spectroscopy (fNIRS) have shown that dual-task walking leads to greater prefrontal cortex (PFC) activation compared to the single-task walking task. However, evidence on age-related changes in PFC activity patterns is inconsistent. Therefore, this study aimed to explore the changes in the activation patterns of PFC subregions in different activation phases (early and late phases) during both single-task and dual-task walking in both older and younger adults.MethodsOverall, 20 older and 15 younger adults performed a walking task with and without a cognitive task. The activity of the PFC subregions in different phases (early and late phases) and task performance (gait and cognitive task) were evaluated using fNIRS and a gait analyzer. ResultsThe gait (slower speed and lower cadence) and cognitive performance (lower total response, correct response and accuracy rate, and higher error rate) of older adults was poorer during the dual task than that of younger adults. Right dorsolateral PFC activity in the early period in older adults was higher than that in younger adults, which declined precipitously during the late period. Conversely, the activity level of the right orbitofrontal cortex in the dual-task for older adults was lower than for younger adults.ConclusionsThese altered PFC subregion-specific activation patterns in older adults would indicate a decline in dual-task performance with aging.

Social play behavior shapes the development of prefrontal inhibition in a region-specific manner.

Experience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex in rats. When these effects of play experience occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the medial prefrontal cortex and the orbitofrontal cortex. We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42), and adult (P85) rats after social play deprivation (between P21 and P42). The development of these prefrontal cortex subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was higher in the orbitofrontal cortex than in the medial prefrontal cortex. Social play deprivation did not affect excitatory currents, but reduced inhibitory transmission in both medial prefrontal cortex and orbitofrontal cortex. Intriguingly, the reduction occurred in the medial prefrontal cortex during social play deprivation, whereas the reduction in the orbitofrontal cortex only became manifested after social play deprivation. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions.

Human ventromedial prefrontal cortex lesions enhance the effect of expectations on pain perception

Pain is strongly modulated by expectations and beliefs. Across species, subregions of ventromedial prefrontal cortex (VMPFC) are implicated in a variety of functions germane to pain, predictions, and learning. Human fMRI studies show that VMPFC activity tracks expectations about pain and mediates expectancy effects on pain-related activity in other brain regions. Prior lesion studies suggest that VMPFC may instead play a more general role in generating affective responses to painful stimuli. To test whether VMPFC is required to generate affective responses to pain or is more specifically involved in expectancy-based pain modulation, we studied responses to heat stimuli in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage. All participants underwent a quantitative sensory testing procedure followed by a pain expectancy task in which cues predicting either low or high pain were followed by intermittent medium intensity heat stimuli. Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expected pain based on predictive cues and failed to update expectations following the covert introduction of unexpected medium temperature stimuli. Consistent with observed expectancy differences, subjective pain unpleasantness ratings in the VMPFC lesion group were more strongly modulated by cue during thermal stimulation. We found no group differences in overall pain sensitivity, nor in relationships between pain and autonomic arousal, suggesting that VMPFC damage specifically enhances the effect of expectations on pain processing, likely driven by impaired integration of new sensory feedback to update expectations about pain. These results provide essential new data regarding the specific functional contribution of VMPFC to pain modulation.

Post-weaning social isolation in male mice leads to abnormal aggression and disrupted network organization in the prefrontal cortex: Contribution of parvalbumin interneurons with or without perineuronal nets

Adverse social experiences during childhood increase the risk of developing aggression-related psychopathologies. The prefrontal cortex (PFC) is a key regulator of social behavior, where experience-dependent network development is tied to the maturation of parvalbumin-positive (PV+) interneurons. Maltreatment in childhood could impact PFC development and lead to disturbances in social behavior during later life. However, our knowledge regarding the impact of early-life social stress on PFC operation and PV+ cell function is still scarce. Here, we used post-weaning social isolation (PWSI) to model early-life social neglect in mice and to study the associated neuronal changes in the PFC, additionally distinguishing between the two main subpopulations of PV+ interneurons, i.e. those without or those enwrapped by perineuronal nets (PNN). For the first time to such detailed extent in mice, we show that PWSI induced disturbances in social behavior, including abnormal aggression, excessive vigilance and fragmented behavioral organization. PWSI mice showed altered resting-state and fighting-induced co-activation patterns between orbitofrontal and medial PFC (mPFC) subregions, with a particularly highly elevated activity in the mPFC. Surprisingly, aggressive interaction was associated with a higher recruitment of mPFC PV+ neurons that were surrounded by PNN in PWSI mice that seemed to mediate the emergence of social deficits. PWSI did not affect the number of PV+ neurons and PNN density, but enhanced PV and PNN intensity as well as cortical and subcortical glutamatergic drive onto mPFC PV+ neurons. Our results suggest that the increased excitatory input of PV+ cells could emerge as a compensatory mechanism for the PV+ neuron-mediated impaired inhibition of mPFC layer 5 pyramidal neurons, since we found lower numbers of GABAergic PV+ puncta on the perisomatic region of these cells. In conclusion, PWSI leads to altered PV-PNN activity and impaired excitatory/inhibitory balance in the mPFC, which possibly contributes to social behavioral disruptions seen in PWSI mice. Our data advances our understanding on how early-life social stress can impact the maturing PFC and lead to the development of social abnormalities in adulthood.

Single-neuron analysis of dendrites and axons reveals the network organization in mouse prefrontal cortex.

The structures of dendrites and axons form the basis for the connectivity of neural network, but their precise relationship at single-neuron level remains unclear. Here we report the complete dendrite and axon morphology of nearly 2,000 neurons in mouse prefrontal cortex (PFC). We identified morphological variations of somata, dendrites and axons across laminar layers and PFC subregions and the general rules of somatodendritic scaling with cytoarchitecture. We uncovered 24 morphologically distinguishable dendrite subtypes in 1,515 pyramidal projection neurons and 405 atypical pyramidal projection neurons and spiny stellate neurons with unique axon projection patterns. Furthermore, correspondence analysis among dendrites, local axons and long-range axons revealed coherent morphological changes associated with electrophysiological phenotypes. Finally, integrative dendrite-axon analysis uncovered the organization of potential intra-column, inter-hemispheric and inter-column connectivity among projection neuron types in PFC. Together, our study provides a comprehensive structural repertoire for the reconstruction and analysis of PFC neural network.

The prelimbic cortex but not the anterior cingulate cortex plays an important role in social recognition and social investigation in mice.

The prefrontal cortex (PFC) has been implicated in social cognitive functions and emotional behaviors in rodents. Each subregion (prelimbic cortex, PL; infralimbic cortex; and anterior cingulate cortex, ACC) of the PFC appears to play a different role in social and emotional behaviors. However, previous investigations have produced inconsistent data, and few previous studies directly compared the roles of the PFC subregions using the same experimental paradigm. Accordingly, in the present study, we examined the role of the PL and the ACC in short-term social recognition, social investigation, and anxiety-related behaviors in C57BL/6J mice. We subjected mice with a lesioned PL or ACC, as well as those in a sham control group, to tests of social recognition and social novelty where juvenile and adult male mice were used as social stimuli. In the social recognition test, the PL-lesioned mice exhibited habituation but not dishabituation regardless of whether they encountered juvenile or adult mice. In a subsequent social novelty test, they spent less time engaged in social investigation compared with the control mice when adult mice were used as social stimuli. These results suggest that PL lesions impaired both social recognition and social investigation. In contrast, ACC-lesioned mice did not exhibit impaired short-term social recognition or social investigation regardless of the social stimulus. Furthermore, PL lesions and ACC lesions did not affect anxiety-related behavior in the open field test or light-dark transition test. Our findings demonstrate that the PL but not the ACC plays an important role in social recognition and social investigation.

Structural covariances of prefrontal subregions selectively associate with dopamine-related gene coexpression and schizophrenia.

Evidence highlights that dopamine (DA) system dysregulation and prefrontal cortex (PFC) dysfunction may underlie the pathophysiology of schizophrenia. However, the associations among DA genes, PFC morphometry, and schizophrenia have not yet been fully clarified. Based on the brain gene expression dataset from Allen Human Brain Atlas and structural magnetic resonance imaging data (NDIS = 1727, NREP = 408), we first identified 10 out of 22 PFC subregions whose gray matter volume (GMV) covariance profiles were reliably associated with their DA genes coexpression profiles, then four out of the identified 10 PFC subregions demonstrated abnormally increased GMV covariance with the hippocampus, insula, and medial frontal areas in schizophrenia patients (NCASE = 100; NCONTROL=102). Moreover, based on a schizophrenia postmortem expression dataset, we found that the DA genes coexpression of schizophrenia was significantly reduced between the middle frontal gyrus and hippocampus, in which 21 DA genes showed significantly unsynchronized expression changes, and the 21 genes' brain expression were enriched in brain activity invoked by working memory, reward, speech production, and episodic memory. Our findings indicate the DA genes selectively regulate the structural covariance of PFC subregions by their coexpression profiles, which may underlie the disrupted GMV covariance and impaired cognitive functions in schizophrenia.

Prefrontal Cortex Hemodynamics and Functional Connectivity Changes during Performance Working Memory Tasks in Older Adults with Sleep Disorders

Older adults with sleep disorders (SDs) show impaired working memory abilities, and working memory processes are closely related to the prefrontal cortex (PFC). However, the neural mechanism of working memory impairment in older adults with SD remains unclear. This study aimed to investigate changes in PFC function among older adults with SD when carrying out the N-back task by functional near-infrared spectroscopy (fNIRS). A total of 37 older adults with SDs were enrolled in this study and matched with 37 healthy older adults by gender, age, and years of education. Changes in PFC function were observed by fNIRS when carrying out the N-back task. The accuracy on the 0-back and 2-back tasks in the SD group was significantly lower than that in the healthy controls (HC) group. The oxygenated hemoglobin (oxy-Hb) concentration of channel 8 which located in the dorsolateral prefrontal cortex (DLPFC) was significantly reduced in the SD group during the 2-back task, and the channel-to-channel connectivity between the PFC subregions was significantly decreased. These results suggest that patients with sleep disorders have a weak performance of working memory; indeed, the activation and functional connectivity in the prefrontal subregions were reduced in this study. This may provide new evidence for working memory impairment and brain function changes in elderly SDs.

Differential processing of decision information in subregions of rodent medial prefrontal cortex.

Decision-making involves multiple cognitive processes requiring different aspects of information about the situation at hand. The rodent medial prefrontal cortex (mPFC) has been hypothesized to be central to these abilities. Functional studies have sought to link specific processes to specific anatomical subregions, but past studies of mPFC have yielded controversial results, leaving the precise nature of mPFC function unclear. To settle this debate, we recorded from the full dorso-ventral extent of mPFC in each of 8 rats, as they performed a complex economic decision task. These data revealed four distinct functional domains within mPFC that closely mirrored anatomically identified subregions, including novel evidence to divide prelimbic cortex into dorsal and ventral components. We found that dorsal aspects of mPFC (ACC, dPL) were more involved in processing information about active decisions, while ventral aspects (vPL, IL) were more engaged in motivational factors.

Profiling prefrontal cortex protein expression in rats exhibiting an incubation of cocaine craving following short-access self-administration procedures.

Incubation of drug-craving refers to a time-dependent increase in drug cue-elicited craving that occurs during protracted withdrawal. Historically, rat models of incubated cocaine craving employed extended-access (typically 6 h/day) intravenous drug self-administration (IV-SA) procedures, although incubated cocaine craving is reported to occur following shorter-access IV-SA paradigms. The notoriously low-throughput of extended-access IV-SA prompted us to determine whether two different short-access IV-SA procedures akin to those in the literature result in qualitatively similar changes in glutamate receptor expression and the activation of downstream signaling molecules within prefrontal cortex (PFC) subregions as those reported previously by our group under 6h-access conditions. For this, adult, male Sprague-Dawley rats were trained to intravenously self-administer cocaine for 2 h/day for 10 consecutive days (2-h model) or for 6 h on day 1 and 2 h/day for the remaining 9 days of training (Mixed model). A sham control group was also included that did not self-administer cocaine. On withdrawal day 3 or 30, rats were subjected to a 2-h test of cue-reinforced responding in the absence of cocaine and a time-dependent increase in drug-seeking was observed under both IV-SA procedures. Immunoblotting of brain tissue collected immediately following the cue test session indicated elevated phospho-Akt1, phospho-CaMKII and Homer2a/b expression within the prelimbic subregion of the PFC of cocaine-incubated rats. However, we failed to detect incubation-related changes in Group 1 metabotropic glutamate receptor or ionotropic glutamate receptor subunit expression in either subregion. These results highlight further a role for Akt1-related signaling within the prelimbic cortex in driving incubated cocaine craving, and provide novel evidence supporting a potential role also for CaMKII-dependent signaling through glutamate receptors in this behavioral phenomenon.

Prelimbic and infralimbic medial prefrontal cortex neuron activity signals cocaine seeking variables across multiple timescales.

The prefrontal cortex is critical for execution and inhibition of reward seeking. Neural manipulation of rodent medial prefrontal cortex (mPFC) subregions differentially impacts execution and inhibition of cocaine seeking. Dorsal, or prelimbic (PL), and ventral, or infralimbic (IL) mPFC are implicated in cocaine seeking or extinction of cocaine seeking, respectively. This differentiation is not seen across all studies, indicating that further research is needed to understand specific mPFC contributions to drug seeking. We recorded neuronal activity in mPFC subregions during cocaine self-administration, extinction, and cue- and cocaine-induced reinstatement of cocaine seeking. Both PL and IL neurons were phasically responsive around lever presses during cocaine self-administration, and activity in both areas was reduced during extinction. During both cue- and, to a greater extent, cocaine-induced reinstatement, PL neurons exhibited significantly elevated responses, in line with previous studies demonstrating a role for the region in relapse. The enhanced PL signaling in cocaine-induced reinstatement was driven by strong excitation and inhibition in different groups of neurons. Both of these response types were stronger in PL vs. IL neurons. Finally, we observed tonic changes in activity in all tasks phases, reflecting both session-long contextual modulation as well as minute-to-minute activity changes that were highly correlated with brain cocaine levels and motivation associated with cocaine seeking. Although some differences were observed between PL and IL neuron activity across sessions, we found no evidence of a go/stop dichotomy in PL/IL function. Instead, our results demonstrate temporally heterogeneous prefrontal signaling during cocaine seeking and extinction in both PL and IL, revealing novel and complex functions for both regions during these behaviors. This combination of findings argues that mPFC neurons, in both PL and IL, provide multifaceted contributions to the regulation of drug seeking and addiction.

Diffusion tensor imaging of superficial prefrontal white matter in healthy aging

The prefrontal cortex (PFC) is a heterogenous structure that is highly susceptible to the effects of aging. Few studies have investigated age effects on the superficial white matter (WM) contained within the PFC using in-vivo magnetic resonance imaging (MRI). This study used diffusion tensor imaging (DTI) tractography to examine the effects of age, sex, and intracranial volume (ICV) on superficial WM within specific PFC subregions, and to model the relationships with age using higher order polynomial regression modelling. PFC WM of 140 healthy individuals, aged 18–85, was segmented into medial and lateral orbitofrontal, medial prefrontal, and dorsolateral prefrontal subregions. Differences due to age in microstructural parameters such as fractional anisotropy (FA), axial and radial diffusivities, and macrostructural measures of tract volumes, fiber counts, average fiber lengths, and average number of fibers per voxel were examined. We found that most prefrontal subregions demonstrated age effects, with decreases in FA, tract volume, and fiber counts, and increases in all diffusivity measures. Age relationships were mostly non-linear, with higher order regressions chosen in most cases. Declines in PFC FA began at the onset of adulthood while the greatest changes in diffusivity and volume did not occur until middle age. The effects of age were most prominent in medial tracts while the lateral orbitofrontal tracts were less affected. Significant effects of sex and ICV were also observed in certain parameters. The patterns mostly followed myelination order, with late-myelinating prefrontal subregions experiencing earlier and more pronounced age effects, further supporting the frontal theory of aging.

Diverging Effects of Adolescent Ethanol Exposure on Tripartite Synaptic Development across Prefrontal Cortex Subregions.

Adolescence is a developmental period that encompasses, but is not limited to, puberty and continues into early adulthood. During this period, maturation and refinement are observed across brain regions such as the prefrontal cortex (PFC), which is critical for cognitive function. Adolescence is also a time when excessive alcohol consumption in the form of binge drinking peaks, increasing the risk of long-term cognitive deficits and the risk of developing an alcohol use disorder later in life. Animal models have revealed that adolescent ethanol (EtOH) exposure results in protracted disruption of neuronal function and performance on PFC-dependent tasks that require higher-order decision-making. However, the role of astrocytes in EtOH-induced disruption of prefrontal cortex-dependent function has yet to be elucidated. Astrocytes have complex morphologies with an extensive network of peripheral astrocyte processes (PAPs) that ensheathe pre- and postsynaptic terminals to form the ‘tripartite synapse.’ At the tripartite synapse, astrocytes play several critical roles, including synaptic maintenance, dendritic spine maturation, and neurotransmitter clearance through proximity-dependent interactions. Here, we investigate the effects of adolescent binge EtOH exposure on astrocyte morphology, PAP-synaptic proximity, synaptic stabilization proteins, and dendritic spine morphology in subregions of the PFC that are important in the emergence of higher cognitive function. We found that adolescent binge EtOH exposure resulted in subregion specific changes in astrocyte morphology and astrocyte-neuronal interactions. While this did not correspond to a loss of astrocytes, synapses, or dendritic spines, there was a corresponding region-specific and EtOH-dependent shift in dendritic spine phenotype. Lastly, we found that changes in astrocyte-neuronal interactions were not a consequence of changes in the expression of key synaptic structural proteins neurexin, neuroligin 1, or neuroligin 3. These data demonstrate that adolescent EtOH exposure results in enduring effects on neuron-glia interactions that persist into adulthood in a subregion-specific PFC manner, suggesting selective vulnerability. Further work is necessary to understand the functional and behavioral implications.

Are the Anterior and Mid-Cingulate Cortices Distinct in Rodents?

The prefrontal cortex (PFC) is involved in cognitive control, emotional regulation, and motivation. In this Perspective article, we discuss the nomenclature of the subdivisions of the medial prefrontal cortex (mPFC), since the anatomical definitions of the PFC subregions have been confusing. Although the mid-cingulate cortex (MCC) and anterior cingulate cortex (ACC) have distinct features in humans and non-human primates, it is unclear whether these regions serve different functions in rodents. Accurate mapping of the cingulate cortex in rodents is important to allow comparisons between species. A proposed change in the nomenclature of the rodent cingulate cortex to anterior cingulate cortex (aCg) and mid-cingulate cortex (mCg) is presented based on our data. We show evidence for distinct cortico-cortical projections from the aCg and mCg to the PrL. The aCg→PrL neurons were abundant in layer VI, while the mCg→PrL neurons were mainly distributed in layer V. In addition, a sex difference was detected in the aCg, with males having a higher proportion of layer V neurons projecting to the PrL than females. Based on this laminar distribution and considering that layer V and VI send efferent projections to different brain areas such as the brain stem, amygdala, and thalamus, we propose that aCg and mCg need to be considered separate entities for future rodent studies. This new definition will put into perspective the role of rodent cingulate cortex in diverse aspects of cognition and facilitate interspecies comparisons in cingulate cortex research.

Decreased Exercise-Induced Changes in Prefrontal Cortex Hemodynamics Are Associated With Depressive Symptoms.

People with a depressed mood tend to perform poorly on executive function tasks, which require much of the prefrontal cortex (PFC), an area of the brain which has also been shown to be hypo-active in this population. Recent research has suggested that these aspects of cognition might be improved through physical activity and cognitive training. However, whether the acute effects of exercise on PFC activation during executive function tasks vary with depressive symptoms remains unclear. To investigate these effects, 106 participants were given a cardiopulmonary exercise test (CPET) and were administered a set of executive function tests directly before and after the CPET assessment. The composite effects of exercise on the PFC (all experimental blocks) showed bilateral activation changes in dorsolateral (BA46/9) and ventrolateral (BA44/45) PFC, with the greatest changes occurring in rostral PFC (BA10). The effects observed in right ventrolateral PFC varied depending on level of depressive symptoms (13% variance explained); the changes in activation were less for higher levels. There was also a positive relationship between CPET scores (VO2peak) and right rostral PFC, in that greater activation changes in right BA10 were predictive of higher levels of aerobic fitness (9% variance explained). Since acute exercise ipsilaterally affected this PFC subregion and the inferior frontal gyrus during executive function tasks, this suggests physical activity might benefit the executive functions these subregions support. And because physical fitness and depressive symptoms explained some degree of cerebral upregulation to these subregions, physical activity might more specifically facilitate the engagement of executive functions that are typically associated with hypoactivation in depressed populations. Future research might investigate this possibility in clinical populations, particularly the neural effects of physical activity used in combination with mental health interventions.

The Impact of HIV Infection in Cocaine Seeking Behaviors

BackgroundSubstance use disorders (SUDs) are characterized by high propensity to relapse and are highly comorbid with HIV infection. The underlying neurobiology of this relationship is poorly understood. Preclinical research on the neurobiobehavioral outcomes of progressive HIV infections may yield crucial information to improve SUD prognosis and reduce risk of relapse in people living with HIV.MethodsTo model progressive HIV, adult male and female C57BL6J mice were inoculated with EcoHIV, a chimeric HIV‐1 which infects murine cells by replacing envelope glycoprotein gp120 with gp80. Five weeks after inoculation mice were trained in a cocaine conditioned place preference (CPP) paradigm (10mg/kg, i.p.) followed by extinction training. Stress‐induced reinstatement was assessed following administration of yohimbine, an α2 adrenergic antagonist, to determine EcoHIV effects. Neuronal activation in the prefrontal cortex (PFC) and nucleus accumbens (NAc) by cocaine exposure was assessed by quantitative analysis the expression of the immediate early gene, cFos.ResultsEcoHIV and sham‐inoculated mice exhibited similar cocaine CPP and extinction. However, EcoHIV mice showed significantly increased yohimbine‐induced reinstatement rate (p<0.05). cFos analysis revealed an elevated neural activation in PFC and NAc in response to cocaine. However, only neurons within infralimbic PFC (IL) and NAc shell subregions showed further increases in activity in cocaine exposed mice infected with EcoHIV vs shams.ConclusionEcoHIV infected mice escalated stress‐induced reinstatement of cocaine seeking compared to controls, suggesting that people living with HIV may be at elevated risk for stress‐induced relapse. Progressive EcoHIV infection may dysregulate IL and NAcShell activity to facilitate the cocaine seeking and reinstatement. Ongoing research will characterize how EcoHIV infection dysregulate IL‐NAcShell pathway specific activity during cocaine reward learning and stress‐induced relapse.

Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood.

Binge alcohol exposure during adolescence results in long-lasting alterations in the brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) that surround some interneurons, particularly PV+ interneurons, further regulate cellular plasticity. The effect of AIE exposure on the expression of these markers within the PFC is not well understood. The present study tested the hypothesis that AIE exposure reduces the expression of PV+ and choline acetyltransferase (ChAT)+ interneurons in the adult PFC and striatum and increases the related expression of PNNs (marked by binding of Wisteria floribunda agglutinin lectin) in adulthood. Male rats were exposed to AIE (5g/kg/day, 2-days-on/2-days-off, i.e., P25 to P54) or water (CON), and brain tissue was harvested in adulthood (>P80). Immunohistochemistry and co-immunofluorescence were used to assess the expression of ChAT, PV, and PNNs within the adult PFC and striatum following AIE exposure. ChAT and PV interneuron densities in the striatum and PFC were unchanged after AIE exposure. However, PNN density in the PFC of AIE-exposed rats was greater than in CON rats. Moreover, significantly more PV neurons were surrounded by PNNs in AIE-exposed subjects than controls in both PFC subregions assessed: orbitofrontal cortex (CON=34%; AIE=40%) and medial PFC (CON=10%; AIE=14%). These findings indicate that, following AIE exposure, PV interneuron expression in the adult PFC and striatum is unaltered, while PNNs surrounding these neurons are increased. This increase in PNNs may restrict the plasticity of the ensheathed neurons, thereby contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

Single-neuron projectome of mouse prefrontal cortex.

Prefrontal cortex (PFC) is the cognitive center that integrates and regulates global brain activity. However, the whole-brain organization of PFC axon projections remains poorly understood. Using single-neuron reconstruction of 6,357 mouse PFC projection neurons, we identified 64 projectome-defined subtypes. Each of four previously known major cortico-cortical subnetworks was targeted by a distinct group of PFC subtypes defined by their first-order axon collaterals. Further analysis unraveled topographic rules of soma distribution within PFC, first-order collateral branch point-dependent target selection and terminal arbor distribution-dependent target subdivision. Furthermore, we obtained a high-precision hierarchical map within PFC and three distinct functionally related PFC modules, each enriched with internal recurrent connectivity. Finally, we showed that each transcriptome subtype corresponds to multiple projectome subtypes found in different PFC subregions. Thus, whole-brain single-neuron projectome analysis reveals organization principles of axon projections within and outside PFC and provides the essential basis for elucidating neuronal connectivity underlying diverse PFC functions.

Thalamo-Prefrontal Connectivity Correlates With Early Command-Following After Severe Traumatic Brain Injury.

Recovery of consciousness after traumatic brain injury (TBI) is heterogeneous and difficult to predict. Structures such as the thalamus and prefrontal cortex are thought to be important in facilitating consciousness. We sought to investigate whether the integrity of thalamo-prefrontal circuits, assessed via diffusion tensor imaging (DTI), was associated with the return of goal-directed behavior after severe TBI. We classified a cohort of severe TBI patients (N = 25, 20 males) into Early and Late/Never outcome groups based on their ability to follow commands within 30 days post-injury. We assessed connectivity between whole thalamus, and mediodorsal thalamus (MD), to prefrontal cortex (PFC) subregions including dorsolateral PFC (dlPFC), medial PFC (mPFC), anterior cingulate (ACC), and orbitofrontal (OFC) cortices. We found that the integrity of thalamic projections to PFC subregions (L OFC, L and R ACC, and R mPFC) was significantly associated with Early command-following. This association persisted when the analysis was restricted to prefrontal-mediodorsal (MD) thalamus connectivity. In contrast, dlPFC connectivity to thalamus was not significantly associated with command-following. Using the integrity of thalamo-prefrontal connections, we created a linear regression model that demonstrated 72% accuracy in predicting command-following after a leave-one-out analysis. Together, these data support a role for thalamo-prefrontal connectivity in the return of goal-directed behavior following TBI.