Frontal Association Cortex Research Articles

Selective Modulation of Fear Memory in Non-Rapid Eye Movement Sleep.

Sleep stabilizes memories for their consolidation, but how to modify specific fear memory during sleep remains unclear. Here, it is reported that using targeted memory reactivation (TMR) to reactivate prior fear learning experience in non-slow wave sleep (NS) inhibits fear memory consolidation, while TMR during slow wave sleep (SWS) enhances fear memory in mice. Replaying conditioned stimulus (CS) during sleep affects sleep spindle occurrence, leading to the reduction or enhancement of slow oscillation-spindle (SO-spindle) coupling in NS and SWS, respectively. Optogenetic inhibition of pyramidal neurons in the frontal association cortex (FrA) during TMR abolishes the behavioral effects of NS-TMR and SWS-TMR by modulating SO-spindle coupling. Notably, calcium imaging of the L2/3 pyramidal neurons in the FrA shows that CS during SWS selectively enhances the activity of neurons previously activated during fear conditioning (FC+ neurons), which significantly correlates with CS-elicited spindle power spectrum density. Intriguingly, these TMR-induced calcium activity changes of FC+ neurons further correlate with mice freezing behavior, suggesting their contributions to the consolidation of fear memories. The findings indicate that TMR can selectively weaken or strengthen fear memory, in correlation with modulating SO-spindle coupling and the reactivation of FC+ neurons during substages of non-rapid eye movement (NREM) sleep.

Functional features of the mirror neuron system during action observation and execution in patients with anxiety and depressive symptoms

The perception and comprehension of non-verbal information and body language in humans and higher primates are realized by the mirror neuron system (MNS). Anxiety and depressive symptoms may change social perception, which could manifest as functional changes in the MNS. In this paper, using the inverse electroencephalography (EEG) problem and rhythm suppression, we investigated spatial and frequency distortions of the MNS in 24 patients exhibiting depressive and anxiety symptoms and 23 controls. EEG was recorded during four motor tasks: action observation (where participants observed a hand gesture performed by a demonstrator), imagination, execution, and joint execution (simultaneous execution with the demonstrator). Mu suppression was employed across a wide frequency and spatial range to assess the level of MNS activity, while the sLORETA method was employed to localize the activity sources. The results indicate that the patients demonstrated task-selective mu suppression mainly during observation and joint execution in the frontal, central, and occipital areas of the cortex across a wide frequency range. In contrast, the controls demonstrated clear and pronounced mu rhythm suppression in the central regions of the brain in the upper-frequency range (10.5 – 13 Hz) during all mirroring tasks. These results suggest that patients with anxiety and depressive symptoms engage additional neural resources to complete social tasks, particularly involving auxiliary neural networks located in the frontal associative arrays and visual cortex.

Effects of olanzapine on hippocampal CA3 and the prefrontal cortex local field potentials

Olanzapine is an antipsychotic drug applied in psychiatry to treat psychoses, especially schizophrenia and schizoaffective disorders with similar or better improvement than haloperidol and risperidone in the treatment of depressive and negative symptoms. The effect of olanzapine on neural synchrony remains to be explored. We investigated the effects of olanzapine on gamma oscillations in the CA3 region of the hippocampus and frontal association cortex. Olanzapine reduced carbachol (CCh)-induced gamma oscillation power in CA3 slice and gamma oscillation power in the frontal association cortex in vivo. The power of theta oscillations was increased in the presence of olanzapine. The phase amplitude coupling of theta and gamma wave was strengthened by the administration of olanzapine in the frontal association cortex in vivo. Taken together, these results show that olanzapine modulates local field potential and the neuronal activity.

A role of frontal association cortex in long-term object recognition memory of objects with complex features in rats.

Perirhinal cortex is a brain area that has been considered crucial for the object recognition memory (ORM). However, with the use of an ORM enhancer named RGS14414 as gain-in-function tool, we show here that frontal association cortex and not the Perirhinal cortex is essential for the ORM of objects with complex features that consisted of detailed drawing on the object surface (complex ORM). An expression of RGS14414, in rat brain frontal association cortex, induced the formation of long-term complex ORM, whereas the expression of the same memory enhancer in Perirhinal cortex failed to produce this effect. Instead, RGS14414 expression in Perirhinal cortex caused the formation of ORM of objects with simple features that consisted of the shape of object (simple ORM). Further, a selective elimination of frontal association cortex neurons by treatment with an immunotoxin Ox7-SAP completely abrogated the formation of complex ORM. Thus, our results suggest that frontal association cortex plays a key role in processing of a high-order recognition memory information in brain.

Engram for the complex signals in the mouse brain: distinct neuronal ensembles for compound conditioning stimulus and its components

Natural learning involves multiple sensory modalities receiving complex stimuli. Elemental learning theories suggest separate encoding and association of each component in a compound signal. Configural theories predict the formation of a representation of the entire complex signal, which is associated with the second event. We developed a mouse model of fear conditioning to a compound tone-light cue or its separate components to test these alternative theories. First, we investigated the memory dynamics of compound cues and their individual components and discovered that they mature at varying times following conditioning. We demonstrated that the memory of the components matures at different intervals after training: memory of the auditory stimulus and the auditory component of CCS is demonstrated behaviorally right after training, whereas memory of the light stimulus and the light component of CCS matures within three days. The memory of CCS, its components, and discrete conditioned stimuli persists for an extended period, up to one month. A similar dissociation was observed in extinction experiments, revealing that the extinction of memory for one CCS component did not affect the memory of the other component when the extinction procedure began a day after training. In addition, when the extinction procedure began seven days after training, while the memory was fully mature, the extinction of one component of contextual conditional stimuli led to the extinction of the other component. Next, c-Fos imaging was conducted to examine cellular activity across multiple brain regions, including the frontal, prelimbic, cingulate, retrosplenial, parietal, primary and secondary visual, primary and secondary auditory cortices, as well as the hippocampus and amygdala. This examination was performed following conditioning using either the entire compound cue or its individual components. We discovered different cortical activation patterns between compound-cue and single-cue conditioning. Conditioning to the compound cue activated prelimbic and frontal associative cortices, whereas single cues did not. Third, we demonstrated that retrieval of memory only through the entire compound cue, and not through single cues, activated the parietal cortex, primary visual cortex, mediolateral secondary visual cortices, and hippocampal CA1. Fourth, through in vivo two-photon imaging, we examined retrieval-induced c-Fos expression in the parietal cortex of fos-EGFP transgenic mice and identified at least three distinct neuronal populations with differential response specificity to the compound signal and its components. Taken together, our data suggest that intricate signals have the potential to establish both integral and elemental neuronal representations. These representations can be used separately in behavior and have different long-term memory dynamics.

Capsaicin alleviates neuronal apoptosis and schizophrenia-like behavioral abnormalities induced by early life stress

Early life stress (ELS) is associated with the later development of schizophrenia. In the rodent model, the maternal separation (MS) stress may induce neuronal apoptosis and schizophrenia-like behavior. Although the TRPV1 agonist capsaicin (CAP) has been reported to reduce apoptosis in the central nervous system, its effect in MS models is unclear. Twenty-four hours of MS of Wistar rat pups on postnatal day (PND9) was used as an ELS. Male rats in the adult stage were the subjects of the study. CAP (1 mg/kg/day) intraperitoneal injection pretreatment was undertaken before behavioral tests for 1 week and continued during the tests. Behavioral tests included open field, novel object recognition, Barnes maze test, and pre-pulse inhibition (PPI) test. MS rats showed behavioral deficits and cognitive impairments mimicking symptoms of schizophrenia compared with controls. MS decreased the expression of TRPV1 in the frontal association cortex (FrA) and in the hippocampal CA1, CA3, and dentate gyrus (DG) regions compared with the control group resulting in the increase of pro-apoptotic proteins (BAX, Caspase3, Cleaved-Caspase3) and the decrease of anti-apoptotic proteins (Bcl-2). The number of NeuN++TUNEL+ cells increased in the MS group in the FrA, CA1, CA3, and DG compared with the control group. Neuronal and behavioral impairments of MS were reversed by treatment with CAP. Exposure to ELS may lead to increased neuronal apoptosis and impaired cognitive function with decreased TRPV1 expression in the prefrontal cortex and hippocampus in adulthood. Sustained low-dose administration of CAP improved neuronal apoptosis and cognitive function. Our results provide evidence for future clinical trials of chili peppers or CAP as dietary supplements for the reversal treatment of schizophrenia.

Altered gray-to-white matter tissue contrast in preterm-born adults.

To investigate cortical organization in brain magnetic resonance imaging (MRI) of preterm-born adults using percent contrast of gray-to-white matter signal intensities (GWPC), which is an in vivo proxy measure for cortical microstructure. Using structural MRI, we analyzed GWPC at different percentile fractions across the cortex (0%, 10%, 20%, 30%, 40%, 50%, and 60%) in a large and prospectively collected cohort of 86 very preterm-born (<32 weeks of gestation and/or birth weight <1500 g, VP/VLBW) adults and 103 full-term controls at 26 years of age. Cognitive performance was assessed by full-scale intelligence quotient (IQ) using the Wechsler Adult Intelligence Scale. GWPC was significantly decreased in VP/VLBW adults in frontal, parietal, and temporal associative cortices, predominantly in the right hemisphere. Differences were pronounced at 20%, 30%, and 40%, hence, in middle cortical layers. GWPC was significantly increased in right paracentral lobule in VP/VLBW adults. GWPC in frontal and temporal cortices was positively correlated with birth weight, and negatively with duration of ventilation (p < 0.05). Furthermore, GWPC in right paracentral lobule was negatively correlated with IQ (p < 0.05). Widespread aberrant gray-to-white matter contrast suggests lastingly altered cortical microstructure after preterm birth, mainly in middle cortical layers, with differential effects on associative and primary cortices.

Functional magnetic resonance imaging study on anxiety and depression disorders induced by chronic restraint stress in rats

Persistent and negative stress stimulation is one of the most important factors leading to anxiety and depression in individuals, and it can negatively affect the normal function and structure of brain-related regions. However, the maladaptive changes of brain neural networks in anxiety and depression induced by chronic stress have not been explored in detail. In this study, we analyzed the changes in global information transfer efficiency, stress related blood oxygen level dependent (BOLD)- and diffusion tensor imaging (DTI)- signals and functional connectivity (FC) in rat models based on resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that compared to control group, rats treated with chronic restraint stress (CRS) for 5 weeks had reconstructed the small-world network properties. In addition, CRS group had increased coherence and activity in bilateral Striatum (ST_R & L), but decreased coherence and activity in unilateral (left) Frontal Association Cortex (FrA_L) and unilateral (left) Medial Entorhinal Cortex (MEC_L). DTI analysis and correlation analysis confirmed the disrupted integrity of MEC_L and ST_R & L and their correlation to anxiety- and depressive-liked behaviors. Functional connectivity further showed these regions of interest (ROI) had decreased positive correlations with several brain areas, respectively. Our study comprehensively revealed the adaptive changes of brain neural networks induced by chronic stress and emphasized the abnormal activity and functional connectivity of ST_R & L and MEC_L in the pathological condition.

Cocaine induces locomotor sensitization through a dopamine-dependent VTA-mPFC-FrA cortico-cortical pathway in male mice

As a central part of the mammalian brain, the prefrontal cortex (PFC) has been implicated in regulating cocaine-induced behaviors including compulsive seeking and reinstatement. Although dysfunction of the PFC has been reported in animal and human users with chronic cocaine abuse, less is known about how the PFC is involved in cocaine-induced behaviors. By using two-photon Ca2+ imaging to simultaneously record tens of intact individual networking neurons in the frontal association cortex (FrA) in awake male mice, here we report that a systematic acute cocaine exposure decreased the FrA neural activity in mice, while the chemogenetic intervention blocked the cocaine-induced locomotor sensitization. The hypoactivity of FrA neurons was critically dependent on both dopamine transporters and dopamine transmission in the ventromedial PFC (vmPFC). Both dopamine D1R and D2R neurons in the vmPFC projected to and innervated FrA neurons, the manipulation of which changed the cocaine-induced hypoactivity of the FrA and locomotor sensitization. Together, this work demonstrates acute cocaine-induced hypoactivity of FrA neurons in awake mice, which defines a cortico-cortical projection bridging dopamine transmission and cocaine sensitization.

Reversal of hyperactive higher-order thalamus attenuates defensiveness in a mouse model of PTSD.

Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating psychiatric disease often accompanied by severe defensive behaviors, preventing individuals from integrating into society. However, the neural mechanisms of defensiveness in PTSD remain largely unknown. Here, we identified that the higher-order thalamus, the posteromedial complex of the thalamus (PoM), was overactivated in a mouse model of PTSD, and suppressing PoM activity alleviated excessive defensive behaviors. Moreover, we found that diminished thalamic inhibition derived from the thalamic reticular nucleus was the major cause of thalamic hyperactivity in PTSD mice. Overloaded thalamic innervation to the downstream cortical area, frontal association cortex, drove abnormal defensiveness. Overall, our study revealed that the malfunction of the higher-order thalamus mediates defensive behaviors and highlighted the thalamocortical circuit as a potential target for treating PTSD-related overreactivity symptoms.

Selective neurodegeneration of the hippocampus caused by chronic cerebral hypoperfusion: F-18 FDG PET study in rats.

Chronic cerebral hypoperfusion (CCH) is known to induce Alzheimer's disease (AD) pathology, but its mechanism remains unclear. The purpose of this study was to identify the cerebral regions that are affected by CCH, and to evaluate the development of AD pathology in a rat model of CCH. A rat model of CCH was established by bilaterally ligating the common carotid arteries in adult male rats (CCH group). The identical operations were performed on sham rats without arteries ligation (control group). Regional cerebral glucose metabolism was evaluated at 1 and 3 months after bilateral CCA ligation using positron emission tomography with F-18 fluorodeoxyglucose. The expression levels of amyloid β40 (Aβ40), amyloid β42 (Aβ42), and hyperphosphorylated tau were evaluated using western blots at 3 months after the ligation. Cognitive function was evaluated using the Y-maze test at 3 months after the ligation. At 1 month after the ligation, cerebral glucose metabolism in the entorhinal, frontal association, motor, and somatosensory cortices were significantly decreased in the CCH group compared with those in the control group. At 3 months after the ligation, cerebral glucose metabolism was normalized in all regions except for the anterodorsal hippocampus, which was significantly decreased compared with that of the control group. The expression of Aβ42 and the Aβ42/40 ratio were significantly higher in the CCH group than those in the control group. The phosphorylated-tau levels of the hippocampus in the CCH group were significantly lower than those in the control group. Cognitive function was more impaired in the CCH group than that in the control group. Our findings suggest that CCH causes selective neurodegeneration of the anterodorsal hippocampus, which may be a trigger point for the development of AD pathology.

Brain Activity after Intermittent Hypoxic Brain Condition in Rats.

Hypoxic brain injury is accompanied by a decrease in various functions. It is also known that obstructive sleep apnea (OSA) can cause hypoxic brain injury. This study aimed to produce a model of an intermittent hypoxic brain condition in rats and determine the activity of the brain according to the duration of hypoxic exposure. Forty male Sprague–Dawley rats were divided into four groups: the control group (n = 10), the 2 h per day hypoxia exposure group (n = 10), the 4 h per day hypoxia exposure group (n = 10), and the 8 h per day hypoxia exposure group (n = 10). All rats were exposed to a hypoxic chamber containing 10% oxygen for five days. Positron emission tomography–computed tomography (PET-CT) brain images were acquired using a preclinical PET-CT scanner to evaluate the activity of brain metabolism. All the rats were subjected to normal conditions. After five days, PET-CT was performed to evaluate the recovery of brain metabolism. Western blot analysis and immunohistochemistry were performed with vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). The mean SUV was elevated in the 2 h per day and 4 h per day groups, and all brain regions showed increased metabolism except the amygdala on the left side, the auditory cortex on the right side, the frontal association cortex on the right side, the parietal association cortex on the right side, and the somatosensory cortex on the right side immediately after hypoxic exposure. However, there was no difference between 5 days rest after hypoxic exposure and control group. Western blot analysis revealed the most significant immunoreactivity for VEGF in the 2, 4, and 8 h per day groups compared with the control group and quantification of VEGF immunohistochemistry showed more expression in 2 and 4 h per day groups compared with the control group. However, there was no significant difference in immunoreactivity for BDNF among the groups. The duration of exposure to hypoxia may affect the activity of the brain due to angiogenesis after intermittent hypoxic brain conditions in rats.

Functional Connectivity in Dorsolateral Frontal Cortex: Intracranial Electroencephalogram Study.

Motivation: Mechanisms underlying the variation in the appearance of electroencephalogram (EEG) over human head are not well characterized. We hypothesized that spatial variation of the EEG, being ultimately linked to variations in cortical neurobiology, was dependent on cortical connectivity patterns. Specifically, we explored the relationship of resting-state functional connectivity derived from intracranial EEG (iEEG) data in seven (N = 7) human epilepsy patients with the intrinsic dynamic variability of the local iEEG. We asked whether primary and association brain areas over the lateral frontal lobe-due to their sharply different connectivity patterns-were thus dissociable in "EEG space." Methods: Functional connectivity between pairs of subdural grid electrodes was averaged to yield an electrode connectivity (EC) whose time-average yielded mean electrode connectivity (mEC), compared with that electrode's time-averaged sample entropy (SE; mean electrode sample entropy, mESE). Results: We found that mEC and mESE were generally in inverse proportion to each other. Extreme values of mEC and mESE occurred over the Rolandic region and were part of a more general rostrocaudal gradient observed in all patients, with larger (smaller) values of mEC (mESE) occurring anteriorly. Conclusions: Brain networks influence brain dynamics. Over the lateral frontal lobe, mEC and mESE demonstrate a rostrocaudal topography, consistent with current notions regarding the structural and functional parcellation of the human frontal lobe. Our findings distinguish the frontal association cortex from primary sensorimotor cortex, effectively "diagnosing" Rolandic iEEG independent of the classical mu rhythm associated with the latter brain region. Impact statement Electroencephalographic rhythms (electroencephalogram [EEG]) exhibit well-recognized spatial variation over the brain surface. How such variation pertains to the biology of the cortex is poorly understood. Here we identify a novel relationship between sample entropy of the local EEG and the connectivity of that local cortical region to the rest of the brain. Due to the differing connectivities of primary and association motor areas, our methods identify new differences in the EEG arising from those respective brain areas. Our work demonstrates that aspects of brain dynamics (i.e., EEG entropy) may be understood in terms of brain architecture (i.e., functional connectivity) and vice versa.

Intracranial Recordings Demonstrate Both Cortical and Medial Temporal Lobe Engagement in Visual Search in Humans.

Visual search is a fundamental human behavior, providing a gateway to understanding other sensory domains as well as the role of search in higher-order cognition. Search has been proposed to include two component processes: inefficient search (Search) and efficient search (Pop-out). According to extant research, these two processes map onto two separable neural systems located in the frontal and parietal association cortices. In this study, we use intracranial recordings from 23 participants to delineate the neural correlates of Search and Pop-out with an unprecedented combination of spatiotemporal resolution and coverage across cortical and subcortical structures. First, we demonstrate a role for the medial temporal lobe in visual search, on par with engagement in frontal and parietal association cortex. Second, we show a gradient of increasing engagement over anatomical space from dorsal to ventral lateral frontal cortex. Third, we confirm previous intracranial work demonstrating nearly complete overlap in neural engagement across cortical regions in Search and Pop-out. We further demonstrate Pop-out selectivity, manifesting as activity increase in Pop-out as compared to Search, in a distributed set of sites including frontal cortex. This result is at odds with the view that Pop-out is implemented in low-level visual cortex or parietal cortex alone. Finally, we affirm a central role for the right lateral frontal cortex in Search.

Characteristics of Regional Cerebral Blood Flow in Alzheimer Disease and Amnestic Mild Cognitive Impairment by Single-Photon Emission Computerized Tomography: A Cross-Sectional Study

Introduction: The regional cerebral blood flow (rCBF) distribution can affect brain functioning, leading to amnestic mild cognitive impairment (aMCI) and mild Alzheimer disease (AD). This study aimed to clarify the detailed characteristics of rCBF distribution in patients with mild AD and aMCI. Methods: This cross-sectional study from April 2015 to March 2018 included 103 older adults (mean age 78.9 years; 60% females), out of a total of 302 adults, and categorized them into 3 groups according to cognitive symptoms. The normal control (NC), aMCI, and mild AD groups included 20, 50, and 33 participants, respectively. The primary outcome was rCBF, which was compared among the 3 groups using a 2-sample t test without correction for multiple comparisons. Results: In the aMCI group, the rCBF decreased in the bilateral parietal and left frontal association cortex and the bilateral premotor cortex (p < 0.01) but increased in the bilateral cerebellum (p < 0.01). In the mild AD group, the rCBF decreased in the bilateral parietal and occipital association cortex, the bilateral premotor cortex, the left temporal and frontal association cortex, and the left limbic lobe (p < 0.01). Conversely, the rCBF increased in some parts of the cerebellum, the bilateral frontal and temporal association cortex, the left occipital association cortex, and the right premotor cortex (p < 0.01). Conclusion: Based on the analysis of the values obtained, it was inferred that the rCBF undergoes reduction and elevation in aMCI and AD patients.

The ventral pathway of the human brain: A continuous association tract system

The brain hemispheres can be divided into an upper dorsal and a lower ventral system. Each system consists of distinct cortical regions connected via long association tracts. The tracts cross the central sulcus or the limen insulae to connect the frontal lobe with the posterior brain. The dorsal stream is associated with sensorimotor mapping. The ventral stream serves structural analysis and semantics in different domains, as visual, acoustic or space processing. How does the prefrontal cortex, regarded as the platform for the highest level of integration, incorporate information from these different domains? In the current view, the ventral pathway consists of several separate tracts, related to different modalities. Originally the assumption was that the ventral path is a continuum, covering all modalities. The latter would imply a very different anatomical basis for cognitive and clinical models of processing. To further define the ventral connections, we used cutting-edge in vivo global tractography on high-resolution diffusion tensor imaging (DTI) data from 100 normal subjects from the human connectome project and ex vivo preparation of fiber bundles in the extreme capsule of 8 humans using the Klingler technique. Our data showed that ventral stream tracts, traversing through the extreme capsule, form a continuous band of fibers that fan out anteriorly to the prefrontal cortex, and posteriorly to temporal, occipital and parietal cortical regions. Introduction of additional volumes of interest in temporal and occipital lobes differentiated between the inferior fronto-occipital fascicle (IFOF) and uncinate fascicle (UF). Unequivocally, in both experiments, in all subjects a connection between the inferior frontal and middle-to-posterior temporal cortical region, otherwise known as the temporo-frontal extreme capsule fascicle (ECF) from nonhuman primate brain-tracing experiments was identified. In the human brain, this tract connects the language domains of “Broca's area” and “Wernicke's area”. The differentiation in the three tracts, IFOF, UF and ECF seems arbitrary, all three pass through the extreme capsule. Our data show that the ventral pathway represents a continuum. The three tracts merge seamlessly and streamlines showed considerable overlap in their anterior and posterior course. Terminal maps identified prefrontal cortex in the frontal lobe and association cortex in temporal, occipital and parietal lobes as streamline endings. This anatomical substrate potentially facilitates the prefrontal cortex to integrate information across different domains and modalities.

Investigating the effects of healthy cognitive aging on brain functional connectivity using 4.7T resting-state functional magnetic resonance imaging.

Functional changes in the aging human brain have been previously reported using functional magnetic resonance imaging (fMRI). Earlier resting-state fMRI studies revealed an age-associated weakening of intra-system functional connectivity (FC) and age-associated strengthening of inter-system FC. However, the majority of such FC studies did not investigate the relationship between age and network amplitude, without which correlation-based measures of FC can be challenging to interpret. Consequently, the main aim of this study was to investigate how three primary measures of resting-state fMRI signal-network amplitude, network topography, and inter-network FC-are affected by healthy cognitive aging. We acquired resting-state fMRI data on a 4.7T scanner for 105 healthy participants representing the entire adult lifespan (18-85years of age). To study age differences in network structure, we combined ICA-based network decomposition with sparse graphical models. Older adults displayed lower blood-oxygen-level-dependent (BOLD) signal amplitude in all functional systems, with sensorimotor networks showing the largest age differences. Our age comparisons of network topography and inter-network FC demonstrated a substantial amount of age invariance in the brain's functional architecture. Despite architecture similarities, old adults displayed a loss of communication efficiency in our inter-network FC comparisons, driven primarily by theFC reduction in frontal and parietal association cortices. Together, our results provide a comprehensive overview of age effects on fMRI-based FC.

Environmental enrichment or selective activation of parvalbumin-expressing interneurons ameliorates synaptic and behavioral deficits in animal models with schizophrenia-like behaviors during adolescence.

Synaptic deficit-induced excitation and inhibition (E/I) imbalance have been implicated in the pathogenesis of schizophrenia. Using in vivo two-photon microscopy, we examined the dynamic plasticity of dendritic spines of pyramidal neurons (PNs) and "en passant" axonal bouton of parvalbumin-expressing interneurons (PVINs) in the frontal association (FrA) cortex in two adolescent mouse models with schizophrenia-like behaviors. Simultaneous imaging of PN dendritic spines and PV axonal boutons showed that repeated exposure to N-methyl-D-aspartate receptor (NMDAR) antagonist MK801 during adolescence disrupted the normal developmental balance of excitatory and inhibitory synaptic structures. This MK801-induced structural E/I imbalance significantly correlated with animal recognition memory deficits and could be ameliorated by environmental enrichment (EE). In addition, selective chemogenetic activation of PVINs in the FrA mimicked the effects of EE on both synaptic plasticity and animal behavior, while selective inhibition of PVIN abolished EE's beneficial effects. Electrophysiological recordings showed that chronic MK801 treatment significantly suppressed the frequency of mEPSC/mIPSC ratio of layer (L) 2/3 PNs and significantly reduced the resting membrane potential of PVINs, the latter was rescued by selective activation of PVINs. Such manipulations of PVINs also showed similar effects in PV-Cre; ErbB4fl/fl animal model with schizophrenia-like behaviors. EE or selective activation of PVINs in the FrA restored behavioral deficits and structural E/I imbalance in adolescent PV-Cre; ErbB4fl/fl mice, while selective inhibition of PVINs abolished EE's beneficial effects. Our findings suggest that the PVIN activity in the FrA plays a crucial role in regulating excitatory and inhibitory synaptic structural dynamics and animal behaviors, which may provide a potential therapeutic target for schizophrenia treatment.

The integration of Gaussian noise by long-range amygdala inputs in frontal circuit promotes fear learning in mice.

Survival depends on the ability of animals to select the appropriate behavior in response to threat and safety sensory cues. However, the synaptic and circuit mechanisms by which the brain learns to encode accurate predictors of threat and safety remain largely unexplored. Here, we show that frontal association cortex (FrA) pyramidal neurons of mice integrate auditory cues and basolateral amygdala (BLA) inputs non-linearly in a NMDAR-dependent manner. We found that the response of FrA pyramidal neurons was more pronounced to Gaussian noise than to pure frequency tones, and that the activation of BLA-to-FrA axons was the strongest in between conditioning pairings. Blocking BLA-to-FrA signaling specifically at the time of presentation of Gaussian noise (but not 8 kHz tone) between conditioning trials impaired the formation of auditory fear memories. Taken together, our data reveal a circuit mechanism that facilitates the formation of fear traces in the FrA, thus providing a new framework for probing discriminative learning and related disorders.

Phosphorylation of GluN2B subunits of N-methyl-d-aspartate receptors in the frontal association cortex involved in morphine-induced conditioned place preference in mice

Morphine is one of the most abused drugs in the world, which has resulted in serious social problems. The frontal association cortex (FrA) has been shown to play a key role in memory formation and drug addiction. N-Methyl-d-aspartate receptors (NMDARs) are abundant in the prefrontal cortex (PFc) and much evidence indicates that GluN2B-containing NMDARs are involved in morphine-induced conditioned place preference (CPP). However, the function of GluN2B in the FrA during morphine-induced CPP has yet to be fully investigated. In the present work, a CPP animal model was employed to measure the expression of phosphorylated (p-) GluN2B (Serine; Ser 1303) in the FrA and NAc in different phases of morphine-induced CPP. We found that p-GluN2B (Ser 1303) was increased in the FrA during the development and reinstatement phases but unchanged in the extinction phase. The use of ifenprodil, a GluN2B-specific antagonist, to block the activity of GluN2B in the two phases attenuated morphine-induced CPP and reinstatement. Furthermore, ifenprodil also blocked morphine-induced upregulation of p-GluN2B (Ser 1303) in the FrA in both phases. These results indicate that GluN2B-containing NMDARs in the FrA may be involved in the regulation of morphine-induced CPP and reinstatement.