Dorsomedial Prefrontal Cortex Research Articles

Working Memory Performance Predicts, but Does Not Reduce, Cocaine and Cannabinoid Seeking in Adult Male Rats.

Cognitive deficits reflecting impaired executive function are commonly associated with psychiatric disorders, including substance use. Cognitive training is proposed to improve treatment outcomes for these disorders by promoting neuroplasticity within the prefrontal cortex, enhancing executive control, and mitigating cognitive decline due to drug use. Additionally, brain derived neurotrophic factor (BDNF) can facilitate plasticity in the prefrontal cortex and reduce drug-seeking behaviors. We investigated whether working memory training could elevate BDNF levels in the prefrontal cortex and if this training would predict or protect against cocaine or cannabinoid seeking. Adult male rats were trained to perform a "simple" or "complex" version of a delayed-match-to-sample working memory task. Rats then self-administered cocaine or the synthetic cannabinoid WIN55,212-2 and were tested for cued drug seeking during abstinence. Tissue from the prefrontal cortex and dorsal hippocampus was analyzed for BDNF protein expression. Training on the working memory task enhanced endogenous BDNF protein levels in the prelimbic prefrontal cortex but not the dorsal hippocampus. Working memory training did not impact self-administration of either drug but predicted the extent of WIN self-administration and cocaine seeking during abstinence. These results suggest that working memory training promotes endogenous BDNF but does not alter drug-seeking or drug-taking behavior. However, individual differences in cognitive performance before drug exposure may predict vulnerability to future drug use.

Electroconvulsive Therapy Regulates the Interhemispheric Functional Connectivity of the Dorsomedial Prefrontal Cortex in Depressive Patients: Evidence from 2 Independent Samples.

The dorsomedial prefrontal cortex (dmPFC) is considered a crucial node in emotional and cognitive processes. Voxel-mirrored homotopic connectivity (VMHC) is a validated methodology for investigating interhemispheric coordination. This study aims to elucidate the effects of electroconvulsive therapy (ECT) on the interhemispheric connectivity of the dmPFC in patients with depression, using VMHC as a measure of bilateral neural coordination. Thirty-three patients with depression, screened at the University of Science and Technology of China (USTC), and thirty-five patients with depression, screened at Anhui Medical University (AHMU), were selected as the subjects of this study. VMHC was employed to investigate the effects of ECT on bilateral hemispheric functional connectivity. The Hamilton Depression Rating Scale (HAMD) was used to assess depressive symptoms, and the relationships between changes in HAMD scores and VMHC values were examined. Following ECT, the depressive symptoms of all participants decreased (p < 0.001). The VMHC values in the dmPFC were significantly increased in both groups after ECT (p < 0.01). No significant correlation was found between the increasing VMHC values in the dmPFC and the changes in HAMD scores in depressed patients (p > 0.05). These results show that ECT regulates interhemispheric functional connectivity in depressed patients, and significantly increases the VMHC values in the dmPFC. Our findings may provide a useful method for optimizing the treatment of depression.

Divergent subregional information processing in mouse prefrontal cortex during working memory

Working memory (WM) is a critical cognitive function allowing recent information to be temporarily held in mind to inform future action. This process depends on coordination between prefrontal cortex (PFC) subregions and other connected brain areas. However, few studies have examined the degree of functional specialization between these subregions throughout WM using electrophysiological recordings in freely-moving mice. Here we record single-units in three neighboring mouse medial PFC (mPFC) subregions—supplementary motor area (MOs), dorsomedial PFC (dmPFC), and ventromedial (vmPFC)—during a freely-behaving non-match-to-position WM task. The MOs is most active around task phase transitions, when it transiently represents the starting sample location. Dorsomedial PFC contains a stable population code, including persistent sample-location-specific firing during the delay period. Ventromedial PFC responds most strongly to reward-related information during choices. Our results reveal subregionally segregated WM computation in mPFC and motivate more precise consideration of the dynamic neural activity required for WM.

Environmental complexity modulates information processing and the balance between decision-making systems.

Behavior in naturalistic scenarios occurs in diverse environments. Adaptive strategies rely on multiple neural circuits and competing decision systems. However, past studies of rodent decision making have largely measured behavior in simple environments. To fill this gap, we recorded neural ensembles from hippocampus (HC), dorsolateral striatum (DLS), and dorsomedial prefrontal cortex (dmPFC) while rats foraged for food under changing rules in environments with varying topological complexity. Environmental complexity increased behavioral variability, lengthened HC nonlocal sequences, and modulated action caching. We found contrasting representations between DLS and HC, supporting a competition between decision systems. dmPFC activity was indicative of setting this balance, in particular predicting the extent of HC non-local coding. Inactivating mPFC impaired short-term behavioral adaptation and produced long-term deficits in balancing decision systems. Our findings reveal the dynamic nature of decision-making systems and how environmental complexity modulates their engagement with implications for behavior in naturalistic environments.

Chronic unpredictable stress during adolescence exerts sex-specific effects on depressive-like behavior and neural activation triggered by tail suspension test

During adolescence, acute stress can modify neuronal excitability in various brain regions, leading to negative behavioral outcomes. However, the impact of chronic stress during adolescence on neuronal responses to acute stimuli remains unclear. To address this, we subjected adolescent mice to 12 days of chronic unpredictable stress (CUS). Anxiety and depressive behaviors were evaluated, along with changes in c-Fos expression, which is one of the most widely used markers of neuronal activation. By comparing c-Fos immunoreactivity between the CUS and control groups both before and after the tail suspension test (TST), we found that adolescent CUS induced depressive behaviors in male mice, but not in female mice. Adolescent CUS primarily affected the excitability of neurons in the infralimbic cortex (IL), the dorsomedial and dorsolateral area of the bed nucleus of the stria terminalis (BNST), and the ventral hippocampus CA3. TST exerted a significant main effect on the density of c-Fos+ neurons in the prelimbic cortex (PL), infralimbic cortex (IL), cingulate areas 1 and 2 (Cg1, Cg2), the lateral septum (LS), Bed nucleus terminalis (BNST), and lateral habenular (LHb). Furthermore, the excitability of neurons in the paraventricular thalamic nucleus (PVT) was impacted by sex. These data suggest that adolescent CUS elicits region- and sex-specific modifications in TST-induced c-Fos expression, establishing a theoretical basis for understanding the pathophysiological alterations in mood disorders following adolescent stress.

Personalised transcranial magnetic stimulation for treatment-resistant depression, depression with comorbid anxiety and negative symptoms of schizophrenia: a narrative review.

Transcranial magnetic stimulation (TMS) is a promising intervention for treatment-resistant psychiatric disorders. However, conventional TMS typically utilises a one-size-fits-all approach when determining stimulation targets. Recent retrospective brain circuit-based analyses using lesion network mapping have suggested that a left dorsal lateral prefrontal cortex target has a higher efficacy for alleviating depression symptoms, a dorsomedial prefrontal cortex target is more effective for anxiety symptoms, and a rostromedial prefrontal cortex target is effective for schizophrenia-associated psychiatric symptoms. Nonetheless, symptom-specific brain circuit targeting has not been tested prospectively. We conducted a narrative review of selected literature to investigate individualised targeting for TMS and discuss potential future directions to elucidate the efficacy of this approach.

Characteristics of locus coeruleus functional connectivity network in patients with comorbid migraine and insomnia

BackgroundMigraine and insomnia are prevalent conditions that often co-occur, each exacerbating the other and substantially impacting the quality of life. The locus coeruleus (LC), a brainstem region responsible for norepinephrine synthesis, participates in pain modulation, sleep/wake cycles, and emotional regulation, rendering it a potential nexus in the comorbidity of migraine and insomnia. Disruptions in the LC-noradrenergic system have been hypothesized to contribute to the comorbidities of migraine and insomnia, although neuroimaging evidence in humans remains scarce. In this study, we aimed to investigate the intrinsic functional connectivity (FC) network of the LC in patients with comorbid migraine and subjective chronic insomnia and patients with migraine with no insomnia (MnI) using resting-state functional magnetic resonance imaging (rs-fMRI) and seed-based FC analyses.MethodsIn this cross-sectional study, 30 patients with comorbid migraine and chronic insomnia (MI), 30 patients with MnI, and 30 healthy controls (HCs) were enrolled. Participants underwent neuropsychological testing and rs-fMRI. The LC-FC network was constructed using seed-based voxel-wise FC analysis. To identify group differences in LC-FC networks, voxel-wise covariance analysis was conducted with sex and age as covariates. Subsequently, a partial correlation analysis was conducted to probe the clinical relevance of aberrant LC-FC in patients with MI and MnI.ResultsExcept for the insomnia score, no other significant difference was detected in demographic characteristics and behavioral performance between the MI and MnI groups. Compared with HCs, patients with MI exhibited altered LC-FC in several brain regions, including the dorsomedial prefrontal cortex (DMPFC), anterior cerebellum, dorsolateral prefrontal cortex (DLPFC), thalamus, and parahippocampal gyrus (PHG). Lower FC between the LC and DLPFC was associated with greater insomnia severity, whereas higher FC between the LC and DMPFC was linked to longer migraine attack duration in the MI group.ConclusionOur findings reveal the presence of aberrant LC-FC networks in patients with MI, providing neuroimaging evidence of the interplay between these conditions. The identified LC-FC alterations may serve as potential targets for therapeutic interventions and highlight the importance of considering the LC-noradrenergic system in the management of MI.

Causal involvement of dorsomedial prefrontal cortex in learning the predictability of observable actions

Social learning is well established across species. While recent neuroimaging studies show that dorsomedial prefrontal cortex (DMPFC/preSMA) activation correlates with observational learning signals, the precise computations that are implemented by DMPFC/preSMA have remained unclear. To identify whether DMPFC/preSMA supports learning from observed outcomes or observed actions, or possibly encodes even a higher order factor (such as the reliability of the demonstrator), we downregulate DMPFC/preSMA excitability with continuous theta burst stimulation (cTBS) and assess different forms of observational learning. Relative to a vertex-cTBS control condition, DMPFC/preSMA downregulation decreases performance during action-based learning but has no effect on outcome-based learning. Computational modeling reveals that DMPFC/preSMA cTBS disrupts learning the predictability, a proxy of reliability, of the demonstrator and modulates the rate of learning from observed actions. Thus, our results suggest that the DMPFC is causally involved in observational action learning, mainly by adjusting the speed of learning about the predictability of the demonstrator.

The Role of the Rat Prefrontal Cortex and Sex Differences in Decision-Making.

The prefrontal cortex is critical for decision-making across species, with its activity linked to choosing between options. Drift Diffusion Models (DDMs) are commonly employed to understand the neural computations underlying this behavior. Studies exploring the specific roles of regions of the rodent prefrontal cortex in controlling the decision process are limited. This study explored the role of the prelimbic cortex (PLC) in decision-making using a two-alternative forced-choice task. Rats first learned to report the location of a lateralized visual stimulus. The brightness of the stimulus indicated its reward value. Then, the rats learned to make choices between pairs of stimuli. Sex differences in learning were observed, with females responding faster and more selectively to high-value stimuli than males. DDM analysis found that males had decreased decision thresholds during initial learning, whereas females maintained a consistently higher drift rate. Pharmacological manipulations revealed that PLC inactivation reduced the decision threshold for all rats, indicating that less information was needed to make a choice in the absence of normal PLC processing. Mu opioid receptor stimulation of the PLC had the opposite effect, raising the decision threshold and reducing bias in the decision process towards high-value stimuli. These effects were observed without any impact on the rats' choice preferences. Our findings suggest that PLC has an inhibitory role in the decision process and regulates the amount of evidence that is required to make a choice. That is, PLC activity controls "when", but not "how", to act.Significance Statement This study reports causal evidence for a part of the rat prefrontal cortex, the prelimbic cortex, in controlling the amount of information needed to make a choice. Results were based on reversible inactivation using the GABA-A agonist muscimol and by stimulation of mu opioid receptors using intra-cortical infusions of the selective mu agonist DAMGO. We also found evidence for a sex difference in learning and performing a visually guided two-alternative forced-choice task. Drift Diffusion Models found that females had stable decision processes throughout learning, and showed a persistent bias against the lower value option. By contrast, males exhibited changes in their decision processes, notably reducing the amount of information needed to make choice over the period of early choice learning.

Histone deacetylase 5 in prelimbic prefrontal cortex limits context-associated cocaine seeking.

Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear. In the rat intravenous cocaine self-administration (SA) model, we examined the role and regulation of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking. To this end, we employed viral molecular tools, chemogenetics, RNA-sequencing, electrophysiology, and immunohistochemistry. In the PrL, reduction of endogenous HDAC5 augmented context-associated, but not cue-or drug prime-reinstated cocaine seeking, whereas overexpression of HDAC5 in PrL, but not IL, reduced context-associated cocaine seeking, but it had no effects on sucrose seeking. In contrast, PrL HDAC5 overexpression following acquisition of cocaine SA had no effects on future cocaine seeking. We found that HDAC5 and cocaine SA altered the expression of numerous PrL genes, including many synapse-associated genes. HDAC5 significantly increased inhibitory synaptic transmission onto PrL deep-layer pyramidal neurons, and it reduced the induction of FOS-positive neurons in the cocaine SA environment. Our findings reveal an essential and selective role for PrL HDAC5 to limit associations formed in cocaine, but not sucrose, SA environments, and that it alters the PrL excitatory/inhibitory balance, possibly through epigenetic regulation of synaptic genes. These results further position HDAC5 as a key factor regulating reward-circuit neuroadaptations that underlie common relapse triggers in SUD.

Neural basis of collective social behavior during environmental challenge.

Humans and animals have a remarkable capacity to collectively coordinate their behavior to respond to environmental challenges. However, the underlying neurobiology remains poorly understood. Here, we found that groups of mice self-organize into huddles at cold ambient temperature during the thermal challenge assay. We found that mice make active (self-initiated) and passive (partner-initiated) decisions to enter or exit a huddle. Using microendoscopic calcium imaging, we found that active and passive decisions are encoded distinctly within the dorsomedial prefrontal cortex (dmPFC). Silencing dmPFC activity in some mice reduced their active decision-making, but also induced a compensatory increase in active decisions by non-manipulated partners, conserving the group's overall huddle time. These findings reveal how collective behavior is implemented in neurobiological mechanisms to meet homeostatic needs during environmental challenges.

Functional network modules overlap and are linked to interindividual connectome differences during human brain development.

The modular structure of functional connectomes in the human brain undergoes substantial reorganization during development. However, previous studies have implicitly assumed that each region participates in one single module, ignoring the potential spatial overlap between modules. How the overlapping functional modules develop and whether this development is related to gray and white matter features remain unknown. Using longitudinal multimodal structural, functional, and diffusion MRI data from 305 children (aged 6 to 14 years), we investigated the maturation of overlapping modules of functional networks and further revealed their structural associations. An edge-centric network model was used to identify the overlapping modules, and the nodal overlap in module affiliations was quantified using the entropy measure. We showed a regionally heterogeneous spatial topography of the overlapping extent of brain nodes in module affiliations in children, with higher entropy (i.e., more module involvement) in the ventral attention, somatomotor, and subcortical regions and lower entropy (i.e., less module involvement) in the visual and default-mode regions. The overlapping modules developed in a linear, spatially dissociable manner, with decreased entropy (i.e., decreased module involvement) in the dorsomedial prefrontal cortex, ventral prefrontal cortex, and putamen and increased entropy (i.e., increased module involvement) in the parietal lobules and lateral prefrontal cortex. The overlapping modular patterns captured individual brain maturity as characterized by chronological age and were predicted by integrating gray matter morphology and white matter microstructural properties. Our findings highlight the maturation of overlapping functional modules and their structural substrates, thereby advancing our understanding of the principles of connectome development.

Microstructural and functional substrates underlying dispositional greed and its link with trait but not state impulsivity

The interplay between personality traits and impulsivity has long been a central theme in psychology and psychiatry. However, the potential association between Greed Personality Traits (GPT) and impulsivity, encompassing both trait and state impulsivity and future time perspective, remains largely unexplored. To address these issues, we employed questionnaires and an inter-temporal choice task to estimate corresponding trait/state impulsivity and collected multi-modal neuroimaging data (resting-state functional imaging: n = 430; diffusion-weighted imaging: n = 426; task-related functional imaging: n = 53) to investigate the underlying microstructural and functional substrates. Behavioral analyses revealed that GPT mediated the association between time perspective (e.g., present fatalism) and trait impulsivity (e.g., motor impulsivity). Functional imaging analyses further identified that brain activation strengths and patterns related to delay length, particularly in the dorsomedial prefrontal cortex, superior parietal lobule, and cerebellum, were associated with GPT. Moreover, individuals with similar levels of greed exhibited analogous spontaneous brain activity patterns, predominantly in the Default Mode Network (DMN), Fronto-Parietal Network (FPN), and Visual Network (VIS). Diffusion imaging analysis observed specific microstructural characteristics in the spinocerebellar/pontocerebellar fasciculus, internal/external capsule, and corona radiata that support the formation of GPT. Furthermore, the corresponding neural activation pattern, spontaneous neural activity pattern, and analogous functional couplings among the aforementioned brain regions mediated the relationships between time perspective and GPT and between GPT and motor impulsivity. These findings provide novel insights into the possible pathway such as time perspective → dispositional greed → impulsivity and uncover their underlying microstructural and functional substrates.

Self-control enhances vigilance performance in temporally irregular tasks: an fNIRS frontoparietal investigation.

The present study investigated whether trait self-control impacted operators' behavior and associated neural resource strategies during a temporally irregular vigilance task. Functional near-infrared spectroscopy (fNIRS) readings of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (HbR) from 29 participants were recorded fromthe prefrontal and parietal cortices. Self-control was associated with better perceptual sensitivity (A') in the task with the irregular event schedule. A left-lateralized effect of HbO2 was found for temporal irregularity within the dorsomedial prefrontal cortex, in accordance with functional transcranial doppler (fTCD) studies. Self-control increased HbR (decreasing activation) at right superior parietal lobule (rSPL; supporting vigilance utilization) and right inferior parietal lobule (rIPL; supporting resource reallocation). However, only rSPL was associated with the vigilance decrement-where decreases in activation led to better perceptual sensitivity in the temporally irregular task. Additionally, short stress-state measures suggest decreases in task engagement in individuals with higher self-control in the irregular task. The authors suggest a trait-state-brain-behavior relationship for self-control during difficult vigilance tasks. Implications for the study include steps toward rectifying the resource utilization vs. allocation debate in vigilance-as well as validating HbO2 and HbR as effective constructs for predicting operators' mental resources through fNIRS.

Impaired emotion recognition in Cntnap2-deficient mice is associated with hyper-synchronous prefrontal cortex neuronal activity.

Individuals diagnosed with autism spectrum disorder (ASD) show difficulty in recognizing emotions in others, a process termed emotion recognition. While human fMRI studies linked multiple brain areas to emotion recognition, the specific mechanisms underlying impaired emotion recognition in ASD are not clear. Here, we employed an emotional state preference (ESP) task to show that Cntnap2-knockout (KO) mice, an established ASD model, do not distinguish between conspecifics according to their emotional state. We assessed brain-wide local-field potential (LFP) signals during various social behavior tasks and found that Cntnap2-KO mice exhibited higher LFP theta and gamma rhythmicity than did C57BL/6J mice, even at rest. Specifically, Cntnap2-KO mice showed increased theta coherence, especially between the prelimbic cortex (PrL) and the hypothalamic paraventricular nucleus, during social behavior. Moreover, we observed significantly increased Granger causality of theta rhythmicity between these two brain areas, across several types of social behavior tasks. Finally, optogenetic stimulation of PrL pyramidal neurons in C57BL/6J mice impaired their social discrimination abilities, including in ESP. Together, these results suggest that increased rhythmicity of PrL pyramidal neuronal activity and its hyper-synchronization with specific brain regions are involved in the impaired emotion recognition exhibited by Cntnap2-KO mice.

A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

Sex differences in contextual fear expression are associated with altered medial prefrontal cortex activity.

Understanding the neural basis of fear expression in rodents has implications for understanding pathological fear responses that characterize posttraumatic stress disorder. Even though posttraumatic stress disorder is more common in females, little is known about the neural circuit interactions supporting fear expression in female rodents. In this study, we were interested in determining whether neural activity associated with the expression of contextual fear differed between males and females within the projections from the medial prefrontal cortex to the ventrolateral periaqueductal gray, and in the medial prefrontal cortex in neurons that do not project to the periaqueductal gray. We infused a viral retrograde tracer into the ventrolateral periaqueductal gray in male and female rats and trained them in a contextual fear conditioning task. The following day rats were re-exposed to the conditioning context and were sacrificed shortly thereafter. Neural activity was measured using EGR1 immunofluorescence. The behavioral results showed that males exhibited higher levels of freezing during the context test than females. Male rats that underwent training and testing showed an increase in the proportion of viral infected cells that express EGR1 in the PL compared to rats that had only received context exposure. Trained female rats were not different than controls, however a direct comparison between sexes was not different. In cells not labeled by the tracer, males showed higher levels of fear-induced EGR1 expression in the prelimbic cortex than females. Conversely, females showed higher levels of EGR1 expression in the infralimbic cortex following testing as compared to males. These results suggest that sex differences in the expression of contextual fear may involve differences in the relative activity levels of the prelimbic and infralimbic cortex.

A distinct neuronal ensemble of prelimbic cortex mediates spontaneous pain in rats with peripheral inflammation

The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.

Toxoplasma gondii Infection of Alzheimer's Disease Mice Reduces Brain Amyloid Density Globally and Regionally.

Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid β plaques. We aimed to determine if there is a brain regional difference in amyloid β reduction in the brains of T. gondii-infected compared to control mice. Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. A brain-wide analysis of amyloid in control and T. gondii-infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration.

Optimal level of human intracranial theta activity for behavioral switching in the subthalamo-medio-prefrontal circuit

The ability to switch between rules associating stimuli and responses depend on a circuit including the dorsomedial prefrontal cortex (dmPFC) and the subthalamic nucleus (STN). However, the precise neural implementations of switching remain unclear. To address this issue, we recorded local field potentials from the STN and from the dmPFC of neuropsychiatric patients during behavioral switching. Drift-diffusion modeling revealed that switching is associated with a shift in the starting point of evidence accumulation. Theta activity increases in dmPFC and STN during successful switch trials, while temporally delayed and excessive levels of theta lead to premature switch errors. This seemingly opposing impact of increased theta in successful and unsuccessful switching is explained by a negative correlation between theta activity and the starting point. Together, these results shed a new light on the neural mechanisms underlying the rapid reconfiguration of stimulus-response associations, revealing a Goldilocks’ effect of theta activity on switching behavior.