Dorsomedial Prefrontal Cortex Research Articles

Diffuse optical tomography for mapping cerebral hemodynamics and functional connectivity in delirium.

Delirium is associated with mortality and new onset dementia, yet the underlying pathophysiology remains poorly understood. Development of imaging biomarkers has been difficult given the challenging nature of imaging delirious patients. Diffuse optical tomography (DOT) offers a promising approach for investigating delirium given its portability and three-dimensional capabilities. Twenty-five delirious and matched non-delirious patients (n=50) were examined using DOT, comparing cerebral oxygenation and functional connectivity in the prefrontal cortex during and after an episode of delirium. Total hemoglobin values were significantly decreased in the delirium group, even after delirium resolution. Functional connectivity between the dorsolateral prefrontal cortex and dorsomedial prefrontal cortex was strengthened post-resolution compared to during an episode; however, this relationship was still significantly weaker compared to controls. These findings highlight DOT's potential as an imaging biomarker to measure impaired cerebral oxygenation and functional dysconnectivity during and after delirium. Future studies should focus on the role of cerebral oxygenation in delirium pathogenesis and exploring the etiological link between delirium and dementias. We developed a portable diffuse optical tomography (DOT) system for bedside three-dimensional functional neuroimaging to study delirium in the hospital. We implemented a novel DOT task-focused seed-based correlation analysis. DOT revealed decreased cerebral oxygenation and functional connectivity strength in the delirium group, even after resolution of delirium.

Involvement of prelimbic cortex neurons and related circuits in the acquisition of a cooperative learning by pairs of rats

AbstractSocial behaviors such as cooperation are crucial for mammals. A deeper knowledge of the neuronal mechanisms underlying cooperation can be beneficial for people suffering from pathologies with impaired social behavior. Our aim was to study the brain activity when two animals synchronize their behavior to obtain a mutual reinforcement. In a previous work, we showed that the activity of the prelimbic cortex (PrL) was enhanced during cooperation in rats, especially in the ones leading most cooperative trials (leader rats). In this study, we investigated the specific cells in the PrL contributing to cooperative behaviors. To this end, we collected rats’ brains at key moments of the learning process to analyze the levels of c-FOS expression in the main cellular groups of the PrL. Leader rats showed increased c-FOS activity in cells expressing D1 receptors during cooperation. Besides, we analyzed the levels of anxiety, dominance, and locomotor behavior, finding that leader rats are in general less anxious and less dominant than followers. We also recorded local field potentials (LFPs) from the PrL, the nucleus accumbens septi (NAc), and the basolateral amygdala (BLA). A spectral analysis showed that delta activity in PrL and NAc increased when rats cooperated, while BLA activity in delta and theta bands decreased considerably during cooperation. The PrL and NAc also increased their connectivity in the high theta band during cooperation. Thus, the present work identifies the specific PrL cell types engaged in this behavior, as well as the way this information is propagated to selected downstream brain regions (BLA, NAc).

CCK+ interneurons contribute to thalamus-evoked feed-forward inhibition in prelimbic prefrontal cortex.

Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feedforward inhibition across mouse cortex, including anterior cingulate cortex, where they are engaged by inputs from mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic cortex (PL), we find that PV+ interneurons are scarce in the principal thalamo-recipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non-fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, peri-somatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feedforward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.Significance Statement Here we use anatomy, slice physiology, and optogenetics to examine how mediodorsal (MD) thalamus evokes feed-forward inhibition in layer 3 of the prelimbic subregion of mouse prefrontal cortex (PFC). We first show that PV+ interneurons are relatively sparse in layer 3 of prelimbic PFC, whereas CCK+ interneurons are prevalent, and we describe the properties of these cells. We then show how MD thalamus preferentially drives a sub-population of fast-spiking CCK+ interneurons to fire more readily than nearby pyramidal cells and other interneurons. Lastly, we show that CCK+ interneurons make peri-somatic inhibitory connections onto pyramidal cells, and both CCK+ and thalamus-evoked inhibition are modulated by CB1 receptors. Our findings identify a novel and unexpected role for CCK+ interneurons in thalamus-evoked inhibition in the PFC.

154. Temporal Interference Stimulation to the Dorsomedial Prefrontal Cortex Potentiates the Effect of Reward on Mood During Effortful Foraging

154. Temporal Interference Stimulation to the Dorsomedial Prefrontal Cortex Potentiates the Effect of Reward on Mood During Effortful Foraging

Nucleus accumbens neuronal ensembles vary with cocaine reinforcement in male and female rats.

Neuronal ensembles in the medial prefrontal cortex mediate cocaine self-administration via projections to the nucleus accumbens. We have recently shown that neuronal ensembles in the prelimbic cortex form rapidly to mediate cocaine self-administration. However, the role of neuronal ensembles within the nucleus accumbens in initial cocaine-seeking behaviour remains unknown. Here, we sought to expand the current literature by testing the necessity of the cocaine self-administration ensemble in the nucleus accumbens core (NAcCore) 1 day after male and female rats acquire cocaine self-administration by using the Daun02 inactivation procedure. We found that disrupting the NAcCore ensembles after a no-cocaine reward-seeking test increased subsequent cocaine seeking, while disrupting NAcCore ensembles following a cocaine self-administration session decreased subsequent cocaine seeking. We then characterized neuronal cell type in the NAcCore using RNAscope in situ hybridization. In the no-cocaine session, we saw reduced dopamine D1 type neuronal activation, while in the cocaine self-administration session, we found preferential dopamine D1 type neuronal activity in the NAcCore.

Circadian Mechanisms of Prefrontal Cortex Dependent Memory in Trace Fear Conditioning

Abstract Circadian rhythms are physiological and behavioral processes that follow an approximately 24-hour cycle. They arise from internal biological clocks, which are synchronized mainly by environmental light. Fear-based mental disorders, such as post-traumatic stress disorder (PTSD), are associated with disruptions in circadian rhythms. Understanding this relationship is important for developing more effective treatments. In delayed fear conditioning, the most common form of fear conditioning, the presentation of a tone (conditioned stimulus) is paired with a foot shock (unconditioned stimulus), causing experimental subjects to associate tone presentation with shock delivery. In trace fear conditioning, a brief temporal gap occurs between the tone and foot shock, causing different brain circuits to get engaged. Past work in our laboratory and others has shown circadian rhythms in the extinction of delayed conditioned fear. More recent work in our laboratory has shown that the recall of trace conditioned fear similarly exhibits a rhythm, with recall being stronger during the inactive phase of the rest-activity cycle. The purpose of this experiment was to test whether stronger recall for trace fear is dependent on the time of conditioning or the time of recall. Additionally, I analyzed brain tissue to assess whether rhythms in behavior were reflected in circadian and activity-dependent gene expression in the prefrontal cortex. Rats were fear conditioned at either ZT4 (the inactive phase) or ZT16 (the active phase) and then underwent fear recall after 24 h (same time of day as training), 36 h (opposite time of day as training), and 48 h (same time of day as training). Results showed an interaction between the time of training and the interval between training and testing for trace fear conditioning. Specifically, ZT4 rats showed strong fear recall at all intervals, whereas ZT16 rats showed increased recall over a greater recall interval. The mRNA expression of Per1, a key circadian gene, showed opposite results, with the ZT4 expression decreasing over recall intervals and ZT16 expression remaining constant. For c-Fos, an immediate early gene whose expression is used to approximate recent neuronal activation, mRNA expression tended to be higher at ZT16 regardless of the time of training. Notably, however, ZT4-36 h rats showed higher c-Fos expression than ZT16-36 h rats in the infralimbic but not prelimbic prefrontal cortex, suggesting differential engagement of the prelimbic cortex during trace fear recall. These results suggest that learned fear may be consolidated more quickly during the inactive phase, leading to signs of prefrontal engagement at later recall intervals during the active phase. In turn, these findings pave the way for circadian assessments, treatments, and prevention for fear-based mental disorders in clinical settings. Lay Summary Circadian rhythms are physiological and behavioral processes that follow an approximately 24-hour cycle. They arise from internal biological clocks, which are synchronized mainly by environmental light. Fear-based mental disorders, such as post-traumatic stress disorder (PTSD), are associated with disruptions in circadian rhythms. Understanding this relationship is important for developing more effective treatments. In trace fear conditioning, a brief temporal gap occurs between the presentation of the tone (conditioned stimulus) and foot shock (unconditioned stimulus). Recent work in our laboratory has shown that the recall of trace conditioned fear exhibits a rhythm, with recall being stronger during the inactive phase of the rest-activity cycle. The purpose of this experiment was to test whether stronger recall for trace fear is dependent on the time of conditioning or the time of recall. Additionally, I analyzed brain tissue to assess whether time-of-day differences in behavior were reflected in circadian and activity-dependent gene expression in the prefrontal cortex. Rats were fear conditioned at either ZT4 (the inactive phase) or ZT16 (the active phase) and thenunderwent fear recall after 24 h, 36 h, and 48 h. Results showed that for behavior the time of testing for trace fear conditioning, ZT4, is what was the most important, and ZT16 rats increase in freezing behavior over a time interval. Per1 mRNA expression in the PFC showed opposite results with the ZT4 expression decreasing over recall intervals and ZT16 expression remaining constant. The time of recall interval was the most important for c-Fos neuronal activity in the PFC. These results show that learned fear behavior is expressed more during the inactive phase training, ZT4, but the neuronal circuitry shows more memory consolidation during the ZT16 recall intervals. These findings suggest that learned fear may be expressed differently through underlying neuronal circuits than through behavior in clinical settings. For the full text, please visit https://scholar.colorado.edu/concern/undergraduate_honors_theses/x059c890d.

Developmental exposure to 17-α-hydroxyprogesterone caproate disrupts decision-making in adult female rats: A potential role for a dopaminergic mechanism

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1–P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms.

Multivariate mapping of low-resilient neurocognitive systems within and around low-grade gliomas.

Accumulating evidence suggests that the brain exhibits a remarkable capacity for functional compensation in response to neurological damage, a resilience potential that is deeply rooted in the malleable features of its underlying anatomo-functional architecture. This propensity is particularly exemplified by diffuse low-grade gliomas (DLGGs), a subtype of primary brain tumour. However, functional plasticity is not boundless, and surgical resections directed at structures with limited neuroplasticity may lead to incapacitating impairments. Yet, maximizing DLGG resections offers substantial oncological benefits, especially when the resection extends beyond the tumour margins (i.e., supra-tumour or supra-total resection). In this context, the primary objective of this study was to identify which cerebral structures were associated with less favourable cognitive outcomes after surgery, while accounting for intra-tumour and supra-tumour features of the surgical resections. To reach this objective, we leveraged a unique cohort of 400 DLGG patients who underwent surgery with awake cognitive mapping. Patients benefited from a neuropsychological assessment consisting of 18 subtests administered before and 3 months post-surgery. We analysed changes in performance and applied topography-focused and disconnection-focused multivariate lesion-symptom mapping (LSM) using support vector regressions with an attempt to capture resected cortico-subcortical structures less amenable to full cognitive compensations. The observed changes in performance were of a limited magnitude suggesting an overall recovery (13/18 tasks fully recovered despite a mean resection extent of 92.4%). Nevertheless, LSM analyses revealed that a lack of recovery in picture naming was linked to damage in the left inferior temporal gyrus and inferior longitudinal fasciculus. Similarly, for semantic fluency abilities, an association was established with damage to the left precuneus/posterior cingulate. For phonologic fluency abilities, the left dorso-medial frontal cortex and the frontal aslant tract were implicated. Moreover, difficulties in spatial exploration were associated with injury to the right dorsomedial prefrontal cortex and its underlying connectivity. An exploratory analysis suggested that supra-tumoral resections were associated with a less pronounced recovery following specific resection patterns, such as supra-tumour resections of the left uncinate fasciculus (picture naming), the left corticostriatal tract and the anterior corpus callosum (phonologic fluency), the hippocampus and para-hippocampus (episodic memory), and the right frontal-mesial areas (visuospatial exploration). Collectively, these patterns of results shed new light on both low-resilient neural systems and the prediction of cognitive recovery following glioma surgery. Furthermore, they indicate that supra-tumour resections were only occasionally less well-tolerated from a cognitive viewpoint. In doing so, they have deep implications for surgical planning and rehabilitation strategies.

Belief updating during social interactions: neural dynamics and causal role of dorsomedial prefrontal cortex.

In competitive interactions, humans have to flexibly update their beliefs about another person's intentions in order to adjust their own choice strategy, such as when believing that the other may exploit their cooperativeness. Here we investigate both the neural dynamics and the causal neural substrate of belief updating processes in humans. We used an adapted prisoner's dilemma task in which participants explicitly predicted the co-player's actions, which allowed us to quantify the prediction error between expected and actual behaviour. First, in a EEG experiment we found a stronger medial frontal negativity (MFN) for negative than positive prediction errors, suggesting that this medial-frontal ERP component may encode unexpected defection of the co-player. The MFN also predicted subsequent belief updating after negative prediction errors. In a second experiment we used transcranial magnetic stimulation (TMS) to investigate whether the dorsomedial prefrontal cortex (dmPFC) causally implements belief updating after unexpected outcomes. Our results show that dmPFC TMS impaired belief updating and strategic behavioural adjustments after negative prediction errors. Taken together, our findings reveal the time-course of the use of prediction errors in social decisions, and suggest that the dmPFC plays a crucial role in updating mental representations of others' intentions.Significance statement For successful social interactions, humans must be able to reliably predict their interaction partners' actions. Previous research has linked this capacity mainly to posterior regions involved in mentalizing. Here, we show that the prefrontal cortex also plays a crucial role for adjusting our beliefs about others' cooperativeness as well: Inhibiting the dorsomedial prefrontal cortex with brain stimulation impaired the ability to modify expectations about the interaction partner's willingness to cooperate. Our findings highlight the role of belief updating for strategic social interactions, and identify the dorsomedial prefrontal cortex and its underlying neural dynamics as neural substrate of the ability to successfully learn others' strategies.

Preliminary evidence for altered brain-heart coherence during anxiogenic movies

Abstract During states of anxiety, fundamental threat circuitry in the brain can increase heart rate via alterations in autonomic balance (increased sympathetic activity and parasympathetic withdrawal) and may serve to promote interoceptive integration and awareness of cardiac signals. Moreover, evidence indicates pathological anxiety could be associated with increased communication between the brain and the heart. Yet, this phenomenon remains not well understood. For instance, studies in this area have been conducted within the confines of tightly controlled experimental paradigms. Whether anxiety impacts brain-heart communication outside of such experimental settings, and in relatively more naturalistic contexts, is less clear. Here, we used a suspenseful movie fMRI paradigm to study induced anxiety (n=29 healthy volunteers; Caltech Conte dataset). We predicted that brain responses across an anxiety-relevant ‘defensive response network’ (amygdala, hypothalamus, periaqueductal gray, bed nucleus of the stria terminalis, dorsomedial prefrontal cortex, ventromedial prefrontal cortex, subgenual anterior cingulate, and anterior insula; Abend et al., 2022) would show increased coherence with heart rate as participants watched a suspenseful movie clip compared to a non-suspenseful movie clip. Counter to our predictions, we found decreased coherence between heart rate and brain responses during increased anxiety, namely in amygdala-prefrontal circuitry. We suggest these alterations may be underpinned by parasympathetic withdrawal and/or decreased interoceptive awareness during suspenseful movie-watching.

Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Increasing CB2 Receptor Activity after Early Life Stress Prevents Depressive Behavior in Female Rats.

Early adversity, the loss of the inhibitory GABAergic interneuron parvalbumin, and elevated neuroinflammation are associated with depression. Individuals with a maltreatment history initiate medicinal cannabis use earlier in life than non-maltreated individuals, suggesting self-medication. Female rats underwent maternal separation (MS) between 2 and 20 days of age to model early adversity or served as colony controls. The prelimbic cortex and behavior were examined to determine whether MS alters the cannabinoid receptor 2 (CB2), which has anti-inflammatory properties. A reduction in the CB2-associated regulatory enzyme MARCH7 leading to increased NLRP3 was observed with Western immunoblots in MS females. Immunohistochemistry with stereology quantified numbers of parvalbumin-immunoreactive cells and CB2 at 25, 40, and 100 days of age, revealing that the CB2 receptor associated with PV neurons initially increases at P25 and subsequently decreases by P40 in MS animals, with no change in controls. Confocal and triple-label microscopy suggest colocalization of these CB2 receptors to microglia wrapped around the parvalbumin neuron. Depressive-like behavior in MS animals was elevated at P40 and reduced with the CB2 agonist HU-308 or a CB2-overexpressing lentivirus microinjected into the prelimbic cortex. These results suggest that increasing CB2 expression by P40 in the prelimbic cortex prevents depressive behavior in MS female rats.

Dorso-medial prefrontal cortex responses to social smiles predict sociability in early human development

Abstract Dorso-medial prefrontal cortex (dmPFC) plays a vital role in social cognition and behavior among humans. Enhanced responses in dmPFC when viewing social scenes predict increased levels of sociability in adults. The current longitudinal study examined the association between dmPFC response and sociability in early development. Brain responses were measured in response to social smiles and frowns using functional near-infrared spectroscopy (fNIRS) at 11 months. Individual differences in sociability were measured using the Early Childhood Behavior Questionnaire (ECBQ) at 18 months. Our longitudinal results show that greater engagement of the dmPFC when processing social smiles, but not frowns, at 11 months predicts higher levels of sociability at 18 months. This demonstrates that early variability in dmPFC response during positive social interactions is linked to individual differences in overtly displayed social behavior. This supports the view that dmPFC plays an important role in social cognition and behavior from early in human ontogeny.

Novel rat model of gaming disorder: assessment of social reward and sex differences in behavior and c-Fos brain activity.

In 2018, the International Classification of Diseases (ICD-11) classified Gaming Disorder (GD) as a mental disorder. GD mainly occurs among adolescents, who, after developing addiction, show psychopathological traits, such as social anxiety, depression, social isolation, and attention deficit. However, the different studies conducted in humans so far show several limitations, such as the lack of demographic heterogeneity and equal representation of age, differences in the type of game and in the follow-up period. Furthermore, at present, no animal models specific to GD are available. To address the lack of an experimental model for GD, in the present work, we proposed a new GD rat model to investigate some peculiar tracts of the disorder. Two-month-old Wistar Kyoto rats, both males and females, were subject to a five-week training with a new innovative touch-screen platform. After five weeks of training, rats were assessed for: (a) their attachment to the play under several conditions, (b) their hyperactivity during gaming, and (c) the maintenance of these conditions after a period of game pause and reward interruption. After sacrifice, using immunohistochemistry techniques, the immunoreactivity of c-Fos (a marker of neuronal activity) was analyzed to study different neural areas. After the training, the rats subjected to GD protocol developed GD-related traits (e.g., hyperactivity, loss control), and the behavioral phenotype was maintained consistently over time. These aspects were completely absent in the control groups. Lastly, the analysis of c-Fos immunoreactivity in prelimbic cortex (PrL), orbitofrontal cortex (OFC), nucleus Accumbens, amygdala and bed nucleus of stria terminalis (BNST) highlighted significant alterations in the GD groups compared to controls, suggesting modifications in neural activity related to the development of the GD phenotype. The proposal of a new GD rat model could represent an innovative tool to investigate, in both sexes, the behavioral and neurobiological features of this disorder, the possible role of external factors in the predisposition and susceptibility and the development of new pharmacological therapies.

Reduced cortical complexity in ventromedial prefrontal cortex is associated with a greater preference for risky and immediate rewards

Abstract In our everyday lives we are often faced with situations in which we make choices that involve risky or delayed rewards. However, the extent to which we are willing to accept larger risky (over smaller certain) or larger delayed (over smaller immediate) rewards varies across individuals. Here we investigated the relationship between cortical complexity in medial prefrontal cortex and individual differences in risky and intertemporal preferences. We found that reduced cortical complexity in left vmPFC was associated with a greater preference for risky and immediate rewards. In addition to these common structural associations in left vmPFC, we also found associations between lower cortical complexity and a greater preference for immediate rewards that extended into left dorsomedial prefrontal cortex and right vmPFC. Furthermore, these structural associations occurred in a context where a preference for risky rewards was correlated with a preference for delayed rewards across individuals. These results suggest that risk and intertemporal preferences are distinct but related, and likely influenced by multiple neurocognitive processes, with cortical complexity in vmPFC reflecting one shared aspect possibly related to impulsiveness in terms of risky and impatient economic choice. Future work should elucidate the complex relationships between brain structure and behavioral preferences.

Neurobiological traces of grief: Examining the impact of offspring loss after birth on rat mothers’ brain and stress-coping behavior in the first week postpartum

The bond between a mother and her infant is one of the strongest social bonds found in mammals. Consequently, the loss of an infant has immense psychological and physiological effects on the caregiver. Despite the significance of this bereavement, only a few studies have investigated the neurobiological impact of offspring loss in mothers. In an approach to fill this gap, we studied the effects of losing all pups the day after giving birth on rat mothers' brain and stress-coping behavior. Specifically, dams experienced 1-, 3-, or 6-days of total offspring loss. We analyzed the neuronal activity and oxytocin receptor (OXT-R) binding in the brain limbic and maternal network regions, as well as the stress response and stress-coping strategies. Following 1 day of loss, the mothers' neuronal activity increased in the limbic system resulting in a positive correlation between the prelimbic cortex and basolateral amygdala, while OXT-R binding was decreased in the central amygdala following up to 3 days of loss. At all three timepoints, plasma corticosterone concentrations did not differ either under basal conditions or following stressor exposure. Remarkably, following 6 days of offspring loss, the mothers showed a significant increase in passive stress-coping behavior, marking the first evidence of offspring loss affects rat mothers' stress-coping behavior. Our results emphasize the significant impact of offspring loss on the mothers’ neuronal activity and brain oxytocin system thereby providing novel insight into the short-term neurobiological traces of grief and paving new avenues for future research in this field.

Prelimbic Cortex-Nucleus Accumbens Core Projection Positively Regulates Itch and Itch-Related Aversion

Itch is one of the most common clinical symptoms in patients with diseases of the skin, liver, or kidney, and it strongly triggers aversive emotion and scratching behavior. Previous studies have confirmed the role of the prelimbic cortex (Prl) and the nucleus accumbens core (NAcC), which are reward and motivation regulatory centers, in the regulation of itch. However, it is currently unclear whether the Prl-NAcC projection, an important pathway connecting these two brain regions, is involved in the regulation of itch and its associated negative emotions. In this study, rat models of acute neck and cheek itch were established by subcutaneous injection of 5-HT, compound 48/80, or chloroquine. Immunofluorescence experiments determined that the number of c-Fos-immunopositive neurons in the Prl increased during acute itch. Chemogenetic inhibition of Prl glutamatergic neurons or Prl-NAcC glutamatergic projections can inhibit both histaminergic and nonhistaminergic itch-scratching behaviors and rectify the itch-related conditioned place aversion (CPA) behavior associated with nonhistaminergic itch. The Prl-NAcC projection may play an important role in the positive regulation of itch-scratching behavior by mediating the negative emotions related to itch.

Brain decoding of spontaneous thought: Predictive modeling of self-relevance and valence using personal narratives

The contents and dynamics of spontaneous thought are important factors for personality traits and mental health. However, assessing spontaneous thoughts is challenging due to their unconstrained nature, and directing participants' attention to report their thoughts may fundamentally alter them. Here, we aimed to decode two key content dimensions of spontaneous thought-self-relevance and valence-directly from brain activity. To train functional MRI-based predictive models, we used individually generated personal stories as stimuli in a story-reading task to mimic narrative-like spontaneous thoughts (n = 49). We then tested these models on multiple test datasets (total n = 199). The default mode, ventral attention, and frontoparietal networks played key roles in the predictions, with the anterior insula and midcingulate cortex contributing to self-relevance prediction and the left temporoparietal junction and dorsomedial prefrontal cortex contributing to valence prediction. Overall, this study presents brain models of internal thoughts and emotions, highlighting the potential for the brain decoding of spontaneous thought.

Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals’ daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.

Parvalbumin interneuron deficiency in the prefrontal and motor cortices of spontaneously hypertensive rats: an attention-deficit hyperactivity disorder animal model insight.

Attention deficit hyperactivity disorder (ADHD) is characterized by impairments in developmental-behavioral inhibition, resulting in impulsivity and hyperactivity. Recent research has underscored cortical inhibition deficiencies in ADHD via the gamma-aminobutyric acid (GABA)ergic system, which is crucial for maintaining excitatory-inhibitory balance in the brain. This study explored postnatal changes in parvalbumin (PV) immunoreactivity, indicating GABAergic interneuron types, in the prefrontal (PFC) and motor (MC) cortices of spontaneously hypertensive rats (SHRs), an ADHD animal model. Examining PV- positive (PV+) cells associated with dopamine D2 receptors (D2) and the impact of dopamine on GABA synthesis, we also investigated changes in the immunoreactivity of D2 and tyrosine hydroxylase (TH). Brain sections from 4- to 10-week-old SHRs and Wistar Kyoto rats (WKYs) were immunohistochemically analyzed, comparing PV+, D2+ cells, and TH+ fiber densities across age-matched SHRs and WKYs in specific PFC/MC regions. The results revealed significantly reduced PV+ cell density in SHRs: prelimbic (~20% less), anterior cingulate (~15% less), primary (~15% less), and secondary motor (~17% less) cortices. PV+ deficits coincided with the upregulation of D2 in prepubertal SHRs and the downregulation of TH predominantly in pubertal/postpubertal SHRs. Reduced PV+ cells in various PFC regions could contribute to inattention/behavioral alterations in ADHD, while MC deficits could manifest as motor hyperactivity. D2 upregulation and TH deficits may impact GABA synthesis, exacerbating behavioral deficits in ADHD. These findings not only shed new light on ADHD pathophysiology but also pave the way for future research endeavors.