Dorsomedial Prefrontal Cortex Research Articles

Uncovering individual variations in bystander intervention of injustice through intrinsic brain connectivity patterns

When confronted with injustice, individuals often intervene as third parties to restore justice by either punishing the perpetrator or helping the victim, even at their own expense. However, little is known about how individual differences in third-party intervention propensity are related to inter-individual variability in intrinsic brain connectivity patterns and how these associations vary between help and punishment intervention. To address these questions, we employed a novel behavioral paradigm in combination with resting-state fMRI and inter-subject representational similarity analysis (IS-RSA). Participants acted as third-party bystanders and needed to decide whether to maintain the status quo or intervene by either helping the disadvantaged recipient (Help condition) or punishing the proposer (Punish condition) at a specific cost. Our analyses focused on three brain networks proposed in the third-party punishment (TPP) model: the salience (e.g., dorsal anterior cingulate cortex, dACC), central executive (e.g., dorsolateral prefrontal cortex, dlPFC), and default mode (e.g., dorsomedial prefrontal cortex, dmPFC; temporoparietal junction, TPJ) networks. IS-RSA showed that individual differences in resting-state functional connectivity (rs-FC) patterns within these networks were associated with the general third-party intervention propensity. Moreover, rs-FC patterns of the right dlPFC and right TPJ were more strongly associated with individual differences in the helping propensity rather than the punishment propensity, whereas the opposite pattern was observed for the dmPFC. Post-hoc predictive modeling confirmed the predictive power of rs-FC in these regions for intervention propensity across individuals. Collectively, these findings shed light on the shared and distinct roles of key regions in TPP brain networks at rest in accounting for individual variations in justice-restoring intervention behaviors.

The claustrum-prelimbic cortex circuit through dynorphin/κ-opioid receptor signaling underlies depression-like behaviors associated with social stress etiology

Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.

Association of executive function with suicidality based on resting-state functional connectivity in young adults with subthreshold depression

Subthreshold depression (StD) is associated an increased risk of developing major depressive disorder (MDD) and suicidality. Suicidality could be linked to distress intolerance and use of context-dependent strategies. We identified neural correlates of executive functioning among the hubs in the resting-state functional connectome (rs-FCN) and examined associations with recent suicidality in StD and MDD. In total, 79 young adults [27 StD, 30 MDD, and 23 healthy controls (HC)] were scanned using magnetic resonance imaging. Neurocognitive measures of the mean latency to correct five moves in the One Touch Stockings of Cambridge (OTSMLC5), spatial working memory between errors (SWMBE), rapid visual information processing A′ (RVPA′), and the stop signal reaction time in the stop signal test (SSTSSRT) were obtained. Global graph metrics were calculated to measure the network integration, segregation, and their balance in the rs-FCN. Regional graph metrics reflecting the number of neighbors (degree centrality; DC), participation in the shortcuts (betweenness centrality; BC), and accessibility to intersections (eigenvector centrality; EC) in the rs-FCN defined group-level hubs for StD, HC, and MDD, separately. Global network metrics were comparable among the groups (all P > 0.05). Among the group-level hubs, regional graph metrics of left dorsal anterior insula (dAI), right dorsomedial prefrontal cortex (dmPFC), right rostral temporal thalamus, right precuneus, and left postcentral/middle temporal/anterior subgenual cingulate cortices were different among the groups. Further, significant associations with neurocognitive measures were found in the right dmPFC with SWMBE, and left dAI with SSTSSRT and RVPA′. Shorter OTSMLC5 was related to the lower centralities of right thalamus and suffer of recent 1-year suicidal ideation (all Ps < 0.05 in ≥ 2 centralities out of DC, BC, and EC). Collectively, salience and thalamic networks underlie spatial strategy and planning, response inhibition, and suicidality in StD and MDD. Anti-suicidal therapies targeting executive function and modulation of salience-thalamic network in StD and MDD are required.

A Pilot Trial of Stepwise Implementation of Virtual Reality Mindfulness and Accelerated Transcranial Magnetic Stimulation Treatments for Dysphoria in Neuropsychiatric Disorders

Dysphoria is a transdiagnostic symptom that causes considerable suffering. Implementation of established self-care and clinical treatment options, such as mindfulness and transcranial magnetic stimulation (TMS), is typically disjointed for conditions involving dysphoria. There is a need for a rapid progression of accessible treatments that can be efficacious across multiple comorbidities. In a pilot stepwise implementation study to assess feasibility and effectiveness, adult participants with dysphoria (depression, anxiety, PTSD, and/or chronic pain) went through a treatment course of VR mindfulness, then accelerated TMS (accel-TMS) over the left dorsolateral prefrontal cortex (left dlPFC), then accel-TMS over the dorsomedial prefrontal cortex (dmPFC). Participants who did not benefit from one treatment phase progressed to the next until remission or study completion. Twenty-four participants were enrolled with 23 in VR mindfulness (phase 1), 19 in accel-TMS left dlPFC (phase 2A), and 13 in accel-TMS dmPFC (phase 2B). For our primary outcome measure of the short form-36 emotional well-being subscale (paired t -test), no significant change was found in phase 1 ( n = 19 , p = .226 ), significant improvement was found in phase 2A ( n = 19 , p = .038 ), and no significant change was found in the smaller sample of phase 2B ( n = 12 , p = .089 ). Symptom improvement was largely supported by clinician-administered scales, with more significant changes found in accel-TMS left dlPFC and dmPFC. The benefits of VR mindfulness were limited; however, both accel-TMS phases showed a significant impact on secondary measures of depression, anxiety, and PTSD. This stepwise protocol shows promise in providing an approach to rapidly improve symptoms of dysphoria in transdiagnostic populations. This trial is registered with NCT05061745.

Cholinergic Activation of Corticofugal Circuits in the Adult Mouse Prefrontal Cortex.

Acetylcholine (ACh) promotes neocortical output to the thalamus and brainstem by preferentially enhancing the postsynaptic excitability of layer 5 pyramidal tract (PT) neurons relative to neighboring intratelencephalic (IT) neurons. Less is known about how ACh regulates the excitatory synaptic drive of IT and PT neurons. To address this question, spontaneous excitatory postsynaptic potentials (sEPSPs) were recorded in dual recordings of IT and PT neurons in slices of prelimbic cortex from adult female and male mice. ACh (20 µM) enhanced sEPSP amplitudes, frequencies, rise-times, and half-widths preferentially in PT neurons. These effects were blocked by the muscarinic receptor antagonist atropine (1 µM). When challenged with pirenzepine (1 µM), an antagonist selective for M1-type muscarinic receptors, ACh instead reduced sEPSP frequencies, suggesting that ACh may generally suppress synaptic transmission in the cortex via non-M1 receptors. Cholinergic enhancement of sEPSPs in PT neurons was not sensitive to antagonism of GABA receptors with gabazine (10 µM) and CGP52432 (2.5 µM) but was blocked by tetrodotoxin (1 µM), suggesting that ACh enhances action-potential-dependent excitatory synaptic transmission in PT neurons. ACh also preferentially promoted the occurrence of synchronous sEPSPs in dual recordings of PT neurons relative to IT-PT and IT-IT parings. Finally, selective chemogenetic silencing of hM4Di-expressing PT, but not commissural IT, neurons blocked cholinergic enhancement of sEPSP amplitudes and frequencies in PT neurons. These data suggest that, in addition to selectively enhancing the postsynaptic excitability of PT neurons, M1 receptor activation promotes corticofugal output by amplifying recurrent excitation within networks of PT neurons.

Diminished Adaptation, Satisfaction, and Neural Responses to Advantageous Social Signals in Anorexia Nervosa and Bulimia Nervosa

BackgroundDevelopment and recurrence of 2 eating disorders (EDs), anorexia nervosa and bulimia nervosa, are frequently associated with environmental stressors. Neurobehavioral responses to social learning signals were evaluated in both EDs. MethodsWomen with anorexia nervosa (n = 25), women with bulimia nervosa (n = 30), or healthy comparison women (n = 38) played a neuroeconomic game in which the norm shifted, generating social learning signals (norm prediction errors [NPEs]) during a functional magnetic resonance imaging scan. A Bayesian logistic regression model examined how the probability of offer acceptance depended on cohort, block, and NPEs. Rejection rates, emotion ratings, and neural responses to NPEs were compared across groups. ResultsRelative to the comparison group, both ED cohorts showed less adaptation (p = .028, ηp2 = 0.060), and advantageous signals (positive NPEs) led to higher rejection rates (p = .014, ηp2 = 0.077) and less positive emotion ratings (p = .004, ηp2 = 0.111). Advantageous signals increased neural activations in the orbitofrontal cortex for the comparison group but not for women with anorexia nervosa (p = .018, d = 0.655) or bulimia nervosa (p = .043, d = 0.527). More severe ED symptoms were associated with decreased activation of dorsomedial prefrontal cortex for advantageous signals. ConclusionsDiminished neural processing of advantageous social signals and impaired norm adaptation were observed in both anorexia nervosa and bulimia nervosa, while no differences were found for disadvantageous social signals. Development of neurocognitive interventions to increase responsivity to advantageous social signals could augment current treatments, potentially leading to improved clinical outcomes for EDs.

The use of theta burst stimulation in patients with schizophrenia - A systematic review.

Transcranial magnetic stimulation (TMS) can offer therapeutic benefits and provide value in neurophysiological research. One of the newer TMS paradigms is theta burst stimulation (TBS) which can be delivered in two patterns: continuous (cTBS - inducing LTD-like effects) and intermittent (iTBS - inducing LTP-like effects). This review paper aims to explore studies that have utilized TBS protocols over different areas of the cortex to study the neurophysiological functions and treatment of patients with schizophrenia. PubMed was searched using the following keywords "schizophrenia", "schizoaffective", or "psychosis", and "theta burst stimulation". Out of the 90 articles which were found, thirty met review inclusion criteria. The inclusion criteria included studying the reported effect (clinical, physiological, or both) of at least one session of TBS on human subjects, and abstracts (at minimum) must have been in English. The main target areas included prefrontal cortex (12 studies - 10 dorsolateral prefrontal cortex (DLPFC), 2 dorsomedial prefrontal cortex (DMPFC)) vermal cerebellum (5), and temporo-parietal cortex (8). Other target areas included inferior parietal lobe (2), and motor cortex (3). TBS neurophysiological effect was explored in 5 studies using functional magnetic resonance image (fMRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), electromyography (EMG) and positron emission topography (PET) scan. Overall, TBS can offer great therapeutic potential as it is well-tolerated, feasible, and has few, if any, adverse effects. TBS may be targeted to treat specific symptomatology, as an augmenting intervention to pharmacotherapy, or even improving patient's insight into their diagnosis.

Prefrontal circuits encode both general danger and specific threat representations.

Behavioral adaptation to potential threats requires both a global representation of danger to prepare the organism to react in a timely manner but also the identification of specific threatening situations to select the appropriate behavioral responses. The prefrontal cortex is known to control threat-related behaviors, yet it is unknown whether it encodes global defensive states and/or the identity of specific threatening encounters. Using a new behavioral paradigm that exposes mice to different threatening situations, we show that the dorsomedial prefrontal cortex (dmPFC) encodes a general representation of danger while simultaneously encoding a specific neuronal representation of each threat. Importantly, the global representation of danger persisted in error trials that instead lacked specific threat identity representations. Consistently, optogenetic prefrontal inhibition impaired overall behavioral performance and discrimination of different threatening situations without any bias toward active or passive behaviors. Together, these data indicate that the prefrontal cortex encodes both a global representation of danger and specific representations of threat identity to control the selection of defensive behaviors.

Functional connectivity between the amygdala and prefrontal cortex underlies processing of emotion ambiguity

Processing facial expressions of emotion draws on a distributed brain network. In particular, judging ambiguous facial emotions involves coordination between multiple brain areas. Here, we applied multimodal functional connectivity analysis to achieve network-level understanding of the neural mechanisms underlying perceptual ambiguity in facial expressions. We found directional effective connectivity between the amygdala, dorsomedial prefrontal cortex (dmPFC), and ventromedial PFC, supporting both bottom-up affective processes for ambiguity representation/perception and top-down cognitive processes for ambiguity resolution/decision. Direct recordings from the human neurosurgical patients showed that the responses of amygdala and dmPFC neurons were modulated by the level of emotion ambiguity, and amygdala neurons responded earlier than dmPFC neurons, reflecting the bottom-up process for ambiguity processing. We further found parietal-frontal coherence and delta-alpha cross-frequency coupling involved in encoding emotion ambiguity. We replicated the EEG coherence result using independent experiments and further showed modulation of the coherence. EEG source connectivity revealed that the dmPFC top-down regulated the activities in other brain regions. Lastly, we showed altered behavioral responses in neuropsychiatric patients who may have dysfunctions in amygdala-PFC functional connectivity. Together, using multimodal experimental and analytical approaches, we have delineated a neural network that underlies processing of emotion ambiguity.

A neuroimaging-based precision medicine framework for depression

BackgroundSymptom-based diagnostic criteria of depression leads to notorious heterogeneity and subjectivity. MethodsThe study was conducted in two stages at two sites: development of a neuroimaging-based subtyping and precise repetitive transcranial magnetic stimulation (rTMS) strategy for depression at Center 1 and its clinical application at Center 2. Center 1 identified depression subtypes and subtype-specific rTMS targets based on amplitude of low frequency fluctuation (ALFF) in a cohort of 238 major depressive disorder patients and 66 healthy controls (HC). Subtypes were identified using a Gaussian Mixture Model, and subtype-specific rTMS targets were selected based on dominant brain regions prominently differentiating depression subtypes from HC. Subsequently, one classifier was employed and 72 hospitalized, depressed youths at Center 2 received two-week precise rTMS. MRI and clinical assessments were obtained at baseline, midpoint, and treatment completion for evaluation. ResultsTwo neuroimaging subtypes of depression, archetypal and atypical depression, were identified based on distinct frontal-posterior functional imbalance patterns as measured by ALFF. The dorsomedial prefrontal cortex was identified as the rTMS target for archetypal depression, and the occipital cortex for atypical depression. Following precise rTMS, ALFF alterations were normalized in both archetypal and atypical depressed youths, corresponding with symptom response of 90.00% in archetypal depression and 70.73% in atypical depression. ConclusionsA precision medicine framework for depression was developed based on objective neurobiomarkers and implemented with promising results, actualizing a subtyping-treatment-evaluation closed loop in depression. Future randomized controlled trials are warranted.

Cognitive empathy mediates the relationship between gray matter volume size of dorsomedial prefrontal cortex and social network size: A voxel-based morphometry study

Social networks are an important factor in developing and maintaining social relationships. The social brain network comprises brain regions that differ in terms of their location, structure, and functioning, and these differences tend to vary among individuals with different social network sizes. However, it remains unknown how social cognitive abilities such as empathy can affect social network size. The goal of our study was to examine the relationship between brain regions in the social brain network, empathy, and individual social network size by using the Social Network Index, which measures social network diversity, size, and complexity by assessing 12 different types of relationships. We performed voxel-based morphometry and mediation analyses using data from questionnaires and structural magnetic resonance imaging data in a sample of 204 young adults. Our findings showed that the gray matter volume of the dorsomedial prefrontal cortex (dmPFC) was inversely associated with social network size and cognitive empathy mediated this association, suggesting that decreased gray matter volume in the dmPFC is associated with greater utilization of cognitive empathy, which, in turn, seems to increase social network size. A potential mechanism explaining this inverse relationship could be cognitive pruning, a phenomenon that occurs in the brain between early adolescence and adulthood, but future longitudinal studies are needed. In conclusion, our findings provide information about the neurocognitive mechanisms involved in the formation and maintenance of social networks.

Effects of Chronic Hydrocodone Exposure and Ceftriaxone on the Expression of Astrocytic Glutamate Transporters in Mesocorticolimbic Brain Regions of C57/BL Mice.

Exposure to opioids can lead to the alteration of several neurotransmitters. Among these neurotransmitters, glutamate is thought to be involved in opioid dependence. Glutamate neurotransmission is mainly regulated by astrocytic glutamate transporters such as glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT). Our laboratory has shown that exposure to lower doses of hydrocodone reduced the expression of xCT in the nucleus accumbens (NAc) and the hippocampus. In the present study, we investigated the effects of chronic exposure to hydrocodone, and tested ceftriaxone as a GLT-1 upregulator in mesocorticolimbic brain regions such as the NAc, the amygdala (AMY), and the dorsomedial prefrontal cortex (dmPFC). Eight-week-old male mice were divided into three groups: (1) the saline vehicle control group; (2) the hydrocodone group; and (3) the hydrocodone + ceftriaxone group. Mice were injected with hydrocodone (10 mg/kg, i.p.) or saline for 14 days. On day seven, the hydrocodone/ceftriaxone group was injected with ceftriaxone (200 mg/kg, i.p.) for last seven days. Chronic exposure to hydrocodone reduced the expression of GLT-1, xCT, protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal Kinase (JNK) in NAc, AMY, and dmPFC. However, hydrocodone exposure increased the expression of G-protein-coupled metabotropic glutamate receptors (mGluR5) in the NAc, AMY, and dmPFC. Importantly, ceftriaxone treatment normalized the expression of mGluR5, GLT-1, and xCT in all these brain regions, except for xCT in the AMY. Importantly, ceftriaxone treatment attenuated hydrocodone-induced downregulation of signaling pathways such as AKT, ERK, and JNK expression in the NAc, AMY, and dmPFC. These findings demonstrate that ceftriaxone has potential therapeutic effects in reversing hydrocodone-induced downregulation of GLT-1 and xCT in selected reward brain regions, and this might be mediated through the downstream kinase signaling pathways such as AKT, ERK, and JNK.

The Causal Role of Temporoparietal Junction in Mediating Self-Other Mergence during Mentalizing.

Mentalizing is a core faculty of human social behaviors that involves inferring the cognitive states of others. This process necessitates adopting an allocentric perspective and suppressing one's egocentric perspective, referred to as self-other distinction (SOD). Meanwhile, individuals may project their own cognitive states onto others in prosocial behaviors, a process known as self-other mergence (SOM). It remains unclear how the two opposing processes coexist during mentalizing. We here combined functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) techniques with intranasal oxytocin (OTint) as a probe to examine the SOM effect in healthy male human participants, during which they attributed the cognitive states of decision confidence to an anonymous partner. Our results showed that OTint facilitated SOM via the left temporoparietal junction (lTPJ), but did not affect neural representations of internal information about others' confidence in the dorsomedial prefrontal cortex, which might be dedicated to SOD, although the two brain regions, importantly, have been suggested to be involved in mentalizing. Further, the SOM effect induced by OTint was fully mediated by the lTPJ activities and became weakened when the lTPJ activities were suppressed by rTMS. These findings suggest that the lTPJ might play a vital role in mediating SOM during mentalizing.SIGNIFICANCE STATEMENT Every human mind is unique. It is critical to distinguish the minds of others from the self. On the contrary, we often project the current mental states of the self onto others; that is to say, self-other mergence (SOM). The neural mechanism underlying SOM remains unclear. We here used intranasal oxytocin (OTint) as a probe to leverage SOM, which is typically suppressed during mentalizing. We revealed that OTint specifically modulated the left temporoparietal junction (lTPJ) neural activities to fully mediate the SOM effect, while suppressing the lTPJ neural activities by transcranial magnetic stimulations causally attenuated the SOM effect. Our results demonstrate that the lTPJ might mediate SOM during social interactions.

Dopamine D1-like receptors modulate synchronized oscillations in the hippocampal–prefrontal–amygdala circuit in contextual fear

Contextual fear conditioning (CFC) is mediated by a neural circuit that includes the hippocampus, prefrontal cortex, and amygdala, but the neurophysiological mechanisms underlying the regulation of CFC by neuromodulators remain unclear. Dopamine D1-like receptors (D1Rs) in this circuit regulate CFC and local synaptic plasticity, which is facilitated by synchronized oscillations between these areas. In rats, we determined the effects of systemic D1R blockade on CFC and oscillatory synchrony between dorsal hippocampus (DH), prelimbic (PL) cortex, basolateral amygdala (BLA), and ventral hippocampus (VH), which sends hippocampal projections to PL and BLA. D1R blockade altered DH–VH and reduced VH–PL and VH–BLA synchrony during CFC, as inferred from theta and gamma coherence and theta-gamma coupling. D1R blockade also impaired CFC, as indicated by decreased freezing at retrieval, which was characterized by altered DH–VH and reduced VH–PL, VH–BLA, and PL–BLA synchrony. This reduction in VH–PL–BLA synchrony was not fully accounted for by non-specific locomotor effects, as revealed by comparing between epochs of movement and freezing in the controls. These results suggest that D1Rs regulate CFC by modulating synchronized oscillations within the hippocampus–prefrontal–amygdala circuit. They also add to growing evidence indicating that this circuit synchrony at retrieval reflects a neural signature of learned fear.

Blame and Praise cross-culturally: An fMRI investigation into causal attribution and moral judgment

People from independent cultures are more likely to causally explain others’ behaviors by their disposition [vs. situation] compared to those from interdependent cultures. However, few studies have directly examined how these differences in attribution shape individuals’ moral judgment, nor the underlying neural mechanisms of this process. Aiming to address these questions, in the scanner, participants rated the blameworthiness or praiseworthiness of protagonists who did either a negative or positive behavior, respectively. These behaviors were pretested and found to be perceived as dispositionally or situationally caused to different extents on average. Regardless of their self-construal, participants showed enhanced dorsomedial prefrontal cortex (dmPFC) activity in response to the behaviors that were evaluated as more situationally caused on average. Importantly, relatively independent participants reduced their blame for the behaviors that they showed greater dmPFC activity to. Relatively interdependent participants reduced blame for the behaviors that they themselves inferred more situational causes for, but dmPFC activity did not explain their blame. These findings suggest that while dmPFC might support relatively independent participants’ effortful consideration of situational contributors to a behavior to make moral judgments, relatively interdependent participants might engage in this process automatically and relied less on dmPFC recruitment.

Temporal association activates projections from the perirhinal cortex and ventral CA1 to the prelimbic cortex and from the prelimbic cortex to the basolateral amygdala.

In trace fear conditioning, the prelimbic cortex exhibits persistent activity during the interval between the conditioned and unconditioned stimuli, which maintains a conditioned stimulus representation. Regions cooperating for this function or encoding the conditioned stimulus before the interval could send inputs to the prelimbic cortex, supporting learning. The basolateral amygdala has conditioned stimulus- and unconditioned stimulus-responsive neurons, convergently activated. The prelimbic cortex could directly project to the basolateral amygdala to associate the transient memory of the conditioned stimulus with the unconditioned stimulus. We investigated the neuronal circuit supporting temporal associations using contextual fear conditioning with a 5-s interval, in which 5s separates the contextual conditioned stimulus from the unconditioned stimulus. Injecting retrobeads, we quantified c-Fos in prelimbic cortex- or basolateral amygdala-projecting neurons from 9 regions after contextual fear conditioning with a 5-s interval or contextual fear conditioning, in which the conditioned and unconditioned stimuli overlap. The contextual fear conditioning with a 5-s interval activated ventral CA1 and perirhinal cortex neurons projecting to the prelimbic cortex and prelimbic cortex neurons projecting to basolateral amygdala. Both fear conditioning activated ventral CA1 and lateral entorhinal cortex neurons projecting to basolateral amygdala and basolateral amygdala neurons projecting to prelimbic cortex. The perirhinal cortex→prelimbic cortex and ventral CA1→prelimbic cortex connections are the first identified prelimbic cortex afferent projections participating in temporal associations. These results help to understand time-linked memories, a process required in episodic and working memories.

Task-based activation and resting-state connectivity predict individual differences in semantic capacity for complex semantic knowledge

Our ability to know and access complex factual information has far reaching effects, influencing our scholastic, professional and social lives. Here we employ functional MRI to assess the relationship between individual differences in semantic aptitude in the task-based activation and resting-state functional connectivity. Using psychometric and behavioural measures, we quantified the semantic and executive aptitude of individuals and had them perform a general-knowledge semantic-retrieval task (N = 41) and recorded resting-state data (N = 43). During the semantic-retrieval task, participants accessed general-knowledge facts drawn from four different knowledge-domains (people, places, objects and ‘scholastic’). Individuals with greater executive capacity more strongly recruit anterior sections of prefrontal cortex (PFC) and the precuneus, and individuals with lower semantic capacity more strongly activate a posterior section of the dorsomedial PFC (dmPFC). The role of these regions in semantic processing was validated by analysis of independent resting-state data, where increased connectivity between a left anterior PFC and the precuneus predict higher semantic aptitude, and increased connectivity between left anterior PFC and posterior dmPFC predict lower semantic aptitude. Results suggest that coordination between core semantic regions in the precuneus and anterior prefrontal regions associated with executive processes support greater semantic aptitude.

Activity-dependent organization of prefrontal hub-networks for associative learning and signal transformation

Associative learning is crucial for adapting to environmental changes. Interactions among neuronal populations involving the dorso-medial prefrontal cortex (dmPFC) are proposed to regulate associative learning, but how these neuronal populations store and process information about the association remains unclear. Here we developed a pipeline for longitudinal two-photon imaging and computational dissection of neural population activities in male mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC network topology. Using regularized regression methods and graphical modeling, we found that fear conditioning drove dmPFC reorganization to generate a neuronal ensemble encoding conditioned responses (CR) characterized by enhanced internal coactivity, functional connectivity, and association with conditioned stimuli (CS). Importantly, neurons strongly responding to unconditioned stimuli during conditioning subsequently became hubs of this novel associative network for the CS-to-CR transformation. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on the activity-dependent formation of the hub network within the dmPFC.

Activation of Beta-adrenergic Receptors Upregulates the Signal-to-Noise Ratio of Auditory Input in the Medial Prefrontal Cortex and Mediates Auditory Fear Conditioning.

Norepinephrine (NE) is involved in auditory fear conditioning (AFC) in posttraumatic stress disorder (PTSD). However, it is still unclear how it acts on neurons. We aimed to investigate whether the activation of the β-adrenergic receptor (β-AR) improves AFC by sensitization of the prelimbic (PL) cortex at the animal, cellular, and molecular levels. In vivo single-cell electrophysiological recording was used to characterize the changes in neurons in the PL cortex after AFC. Then, PL neurons were locally administrated by the β-AR agonist isoproterenol (ISO), the GABAaR agonist muscimol, or intervened by optogenetic method, respectively. Western blotting and immunohistochemistry were finally used to assess molecular changes. Noise and low-frequency tones induced similar AFC. The expression of β-ARs in PL cortex neurons was upregulated after fear conditioning. Microinjection of muscimol into the PL cortex blocked the conformation of AFC, whereas ISO injection facilitated AFC. Moreover, PL neurons can be distinguished into two types, with type I but not type II neurons responding to conditioned sound and being regulated by β-ARs. Our results showed that β-ARs in the PL cortex regulate conditional fear learning by activating type I PL neurons.

Modulatory Effects of Communicative Gaze on Attentional Orienting Are Driven by Dorso-medial Prefrontal Cortex but Not Right Temporoparietal Junction.

Communicative gaze (e.g., mutual or averted) has been shown to affect attentional orienting. However, no study to date has clearly separated the neural basis of the pure social component that modulates attentional orienting in response to communicative gaze from other processes that might be a combination of attentional and social effects. We used TMS to isolate the purely social effects of communicative gaze on attentional orienting. Participants completed a gaze-cueing task with a humanoid robot who engaged either in mutual or in averted gaze before shifting its gaze. Before the task, participants received either sham stimulation (baseline), stimulation of right TPJ (rTPJ), or dorso-medial prefrontal cortex. Results showed, as expected, that communicative gaze affected attentional orienting in baseline condition. This effect was not evident for rTPJ stimulation. Interestingly, stimulation to rTPJ also canceled out attentional orienting altogether. On the other hand, dorso-medial prefrontal cortex stimulation eliminated the socially driven difference in attention orienting between the two gaze conditions while maintaining the basic general attentional orienting effect. Thus, our results allowed for separation of the pure social effect of communicative gaze on attentional orienting from other processes that are a combination of social and generic attentional components.