Electroacupuncture attenuates neuropathic pain via suppressing BIP-IRE-1α-mediated endoplasmic reticulum stress in the anterior cingulate cortex.

Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.

Abnormal functional neurocircuitry underpinning emotional processing in fibromyalgia.

Fibromyalgia, a condition characterized by chronic pain, is frequently accompanied by emotional disturbances. Here we aimed to study brain activation and functional connectivity (FC) during processing of emotional stimuli in fibromyalgia. Thirty female patients with fibromyalgia and 31 female healthy controls (HC) were included. Psychometric tests were administered to measure alexithymia, affective state, and severity of depressive and anxiety symptoms. Next, participants performed an emotion processing and regulation task during functional magnetic resonance imaging (fMRI). We performed a 2 × 2 ANCOVA to analyze main effects and interactions of the stimuli valence (positive or negative) and group (fibromyalgia or HC) on brain activation. Generalized psychophysiological interaction analysis was used to assess task-dependent FC of brain regions previously associated with emotion processing and fibromyalgia (i.e., hippocampus, amygdala, anterior insula, and pregenual anterior cingulate cortex [pACC]). The left superior lateral occipital cortex showed more activation in fibromyalgia during emotion processing than in HC, irrespective of valence. Moreover, we found an interaction effect (valence x group) in the FC between the left pACC and the precentral and postcentral cortex, and central operculum, and premotor cortex. These results suggest abnormal brain activation and connectivity underlying emotion processing in fibromyalgia, which could help explain the high prevalence of psychopathological symptoms in this condition.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS)

Objective: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. Methods: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. Results: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Conclusions: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials. Registration number: PROSPERO CRD42022296246.

Radiofrequency Cingulotomy as a Treatment for Incoercible Pain: Follow-Up for 6 Months.

Incoercible or intractable pain is defined as pain that is refractory to pharmacological treatment to such an extent that opioid and analgesic adverse effects outweigh the therapeutic effects. The anterior cingulate cortex (ACC) is involved in the perception of pain, especially emotional pain, so it is logical that cingulotomy has an effective therapeutic effect. Therefore, we evaluated the effectiveness of cingulotomy for the treatment of incoercible pain. An observational, longitudinal, retrospective, and analytical study was carried out on a series of cases in which bilateral cingulotomy was performed for incoercible pain, and follow-up was performed 6 months after neurosurgery in the outpatient clinic at the Neurotraumatology Clinic. A positive correlation was observed between pain intensity and medication use, indicating that an increase in pain was associated with a greater requirement for analgesics. The result was a significant reduction in pain, as measured by the visual analog scale of pain, and decreased drug use after cingulotomy. We concluded that cingulotomy reduces incoercible pain and the need for medication.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS).

OBJECTIVE: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. METHODS: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. RESULTS: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. CONCLUSION: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials.

Plasticity of Cortico-striatal Neurons of the Caudal Anterior Cingulate Cortex During Experimental Neuropathic Pain.

Maladaptive neuronal plasticity is a main mechanism for the development and maintenance of pathological pain. Affective, motivational and cognitive deficits that are comorbid with pain involve cellular and synaptic modifications in the anterior cingulate cortex (ACC), a major brain mediator of pain perception. Here we use a model of neuropathic pain (NP) in male mice and ex-vivo electrophysiology to investigate whether layer 5 caudal ACC (cACC) neurons projecting to the dorsomedial striatum (DMS), a critical region for motivational regulation of behavior, are involved in aberrant neuronal plasticity. We found that while the intrinsic excitability of cortico-striatal cACC neurons (cACC-CS) was preserved in NP animals, excitatory postsynaptic potentials (EPSP) induced after stimulation of distal inputs were enlarged. The highest synaptic responses were evident both after single stimuli and in each of the EPSP that compose responses to trains of stimuli, and were accompanied by increased synaptically-driven action potentials. EPSP temporal summation was intact in ACC-CS neurons from NP mice, suggesting that the plastic changes were not due to alterations in dendritic integration but rather through synaptic mechanisms. These results demonstrate for the first time that NP affects cACC neurons that project to the DMS and reinforce the notion that maladaptive plasticity of the cortico-striatal pathway may be a key factor in sustaining pathological pain.

Frontolimbic Network Topology Associated With Risk and Presence of Depression in Adolescents: A Study Using a Composite Risk Score in Brazil.

BACKGROUND: There have been significant challenges in understanding functional brain connectivity associated with adolescent depression, including the need for a more comprehensive approach to defining risk, the lack of representation of participants from low- and middle-income countries, and the need for network-based approaches to model connectivity. The current study aimed to address these challenges by examining resting-state functional connectivity of frontolimbic circuitry associated with the risk and presence of depression in adolescents in Brazil. METHODS: Adolescents in Brazil ages 14 to 16 years were classified into low-risk, high-risk, and depressed groups using a clinical assessment and composite risk score that integrates 11 sociodemographic risk variables. After excluding participants with excessive head movement, resting-state functional magnetic resonance imaging data of 126 adolescents were analyzed. We compared group differences in frontolimbic network connectivity using region of interest-to-region of interest, graph theory, and seed-based connectivity analyses. Associations between self-reported depressive symptoms and brain connectivity were also explored. RESULTS: Adolescents with depression showed greater dorsal anterior cingulate cortex (ACC) connectivity with the orbitofrontal cortex compared with the 2 risk groups and greater dorsal ACC global efficiency than the low-risk group. Adolescents with depression also showed reduced local efficiency and a lower clustering coefficient of the subgenual ACC compared with the 2 risk groups. The high-risk group also showed a lower subgenual ACC clustering coefficient relative to the low-risk group. CONCLUSIONS: These findings highlight altered connectivity and topology of the ACC within frontolimbic circuitry as potential neural correlates and risk factors of developing depression in adolescents in Brazil. This study broadens our understanding of the neural connectivity associated with adolescent depression in a global context.

Von Economo neurons: Cellular specialization of human limbic cortices?

Von Economo neurons (VENs) have been mentioned in the medical literature since the second half of the 19th century; however, it was not until the second decade of the 20th century that their cytomorphology was described in detail. To date, VENs have been found in limbic sectors of the frontal, temporal and insular lobes. In humans, their density seems to decrease in the caudo-rostral and ventro-dorsal direction; that is, from the anterior regions of the cingulate and insular cortices towards the frontal pole and the superior frontal gyrus. Several studies have provided similar descriptions of the shape of the VEN soma, but the size of the soma varies from one cortical region to another. There is consensus among different authors about the selective vulnerability of VENs in certain pathologies, in which a deterioration of the capacities involved in social behaviour is observed. In this review, we propose that the restriction of VENs towards the sectors linked to limbic information processing in Homo sapiens gives them a possible functional role in relation to the structures in which they are located. However, given the divergence in characteristics such as location, density, size and biochemical profile among VENs of different cortical sectors, the activities in which they participate could allow them to partake in a wide spectrum of neurological functions, including autonomic responses and executive functions.

Anterior cingulate cortex, but not amygdala, modulates the anxiogenesis induced by living with conspecifics subjected to chronic restraint stress in male mice.

Cohabitation with a partner undergoing chronic restraint stress (CRE) induces anxiogenic-like behaviors through emotional contagion. We hypothesized that the anterior cingulate cortex (ACC) and the amygdala would be involved in the modulation of this emotional process. This study investigated the role of the ACC and amygdala in empathy-like behavior (e.g., anxiety-like responses) induced by living with a mouse subjected to CRE. Male Swiss mice were housed in pairs for 14 days and then allocated into two groups: cagemate stress (one animal of the pair was subjected to 14 days of restraint stress) and cagemate control (no animal experienced stress). Twenty-four hours after the last stress session, cagemates had their brains removed for recording FosB labeling in the ACC and amygdala (Exp.1). In experiments 2 and 3, 24 h after the last stress session, the cagemates received 0.1 µL of saline or cobalt chloride (CoCl2 1 mM) into the ACC or amygdala, and then exposed to the elevated plus-maze (EPM) for recording anxiety. Results showed a decrease of FosB labeling in the ACC without changing immunofluorescence in the amygdala of stress cagemate mice. Cohabitation with mice subjected to CRE provoked anxiogenic-like behaviors. Local inactivation of ACC (but not the amygdala) reversed the anxiogenic-like effects induced by cohabitation with a partner undergoing CRE. These results suggest the involvement of ACC, but not the amygdala, in anxiety induced by emotional contagion.

Cerebral Responses to Stationary Emotional Stimuli Measured by fMRI in Women with Persistent Postural-Perceptual Dizziness

Abstract Introduction Persistent postural-perceptual dizziness (PPPD) is a functional vestibular disorder characterized by chronic dizziness, unsteadiness, and hypersensitivity to motion. Preexisting anxiety disorders and neurotic personality traits confer vulnerability to PPPD. High anxiety during acute vertigo or dizziness incites it. A functional magnetic resonance imaging (fMRI) study of chronic subjective dizziness found unexpectedly hypoactive responses to vestibular stimulation in cortical regions that integrate threat assessment and spatial perception. Objective This fMRI study used non-moving, but emotionally charged visual stimuli to investigate the brain's activity of PPPD patients and control subjects. Methods The participants included 16 women with PPPD and 16 age-matched women who recovered completely from acute episodes of vertigo or dizziness capable of triggering PPPD. Brain responses to positive, neutral, and negative figures from the International Affective Picture System were measured with fMRI and compared between the groups. Dizziness handicap, anxiety, and depression were assessed with validated questionnaires. Results Between group analyses: Participants with PPPD showed reduced activity in anterior cingulate cortex and increased activity in left angular gyrus in response to negative versus positive stimuli, which was not observed in recovered individuals. Within group analyses: Participants with PPPD had increased activity in visuospatial areas (parahippocampal gyrus, intraparietal sulcus) in negative versus positive and negative versus neutral contrasts, whereas recovered individuals had increased activity in anxiety regions (amygdala, orbitofrontal cortex). Conclusion Patients with PPPD may be more attuned to spatial elements than to the content of emotionally charged visual stimuli.

Cerebral Responses to Stationary Emotional Stimuli Measured by fMRI in Women with Persistent Postural-Perceptual Dizziness.

Introduction Persistent postural-perceptual dizziness (PPPD) is a functional vestibular disorder characterized by chronic dizziness, unsteadiness, and hypersensitivity to motion. Preexisting anxiety disorders and neurotic personality traits confer vulnerability to PPPD. High anxiety during acute vertigo or dizziness incites it. A functional magnetic resonance imaging (fMRI) study of chronic subjective dizziness found unexpectedly hypoactive responses to vestibular stimulation in cortical regions that integrate threat assessment and spatial perception. Objective This fMRI study used non-moving, but emotionally charged visual stimuli to investigate the brain's activity of PPPD patients and control subjects. Methods The participants included 16 women with PPPD and 16 age-matched women who recovered completely from acute episodes of vertigo or dizziness capable of triggering PPPD. Brain responses to positive, neutral, and negative figures from the International Affective Picture System were measured with fMRI and compared between the groups. Dizziness handicap, anxiety, and depression were assessed with validated questionnaires. Results Between group analyses: Participants with PPPD showed reduced activity in anterior cingulate cortex and increased activity in left angular gyrus in response to negative versus positive stimuli, which was not observed in recovered individuals. Within group analyses: Participants with PPPD had increased activity in visuospatial areas (parahippocampal gyrus, intraparietal sulcus) in negative versus positive and negative versus neutral contrasts, whereas recovered individuals had increased activity in anxiety regions (amygdala, orbitofrontal cortex). Conclusion Patients with PPPD may be more attuned to spatial elements than to the content of emotionally charged visual stimuli.

Histamine and Corticosterone Modulate Acid Sensing Ion Channels (ASICs) Dependent Long-term Potentiation at the Mouse Anterior Cingulate Cortex.

Increase in proton concentration [H+] or decrease in local and global extracellular pH occurs in both physiological and pathological conditions. Acid-sensing ion channels (ASICs), belonging to the ENaC/Deg superfamily, play an important role in signal transduction as proton sensor. ASICs and in particular ASIC1a (one of the six ASICs subunits) which is permeable to Ca2+, are involved in many physiological processes including synaptic plasticity and neurodegenerative diseases. Activity-dependent long-term potentiation (LTP) is a major type of long-lasting synaptic plasticity in the CNS, associated with learning, memory, development, fear and persistent pain. Neurons in the anterior cingulate cortex (ACC) play critical roles in pain perception and chronic pain and express ASIC1a channels. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H+ from synaptic vesicles activates postsynaptic ASIC1a channels in ACC of mice. This generates ASIC1a synaptic currents that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that modulators like histamine and corticosterone, acting through ASIC1a regulate synaptic plasticity, reducing the threshold for LTP induction of glutamatergic EPSCs. Our findings suggest a new role for ASIC1a mediating the neuromodulator action of histamine and corticosterone regulating specific forms of synaptic plasticity in the mouse ACC.

Differential modulation of the anterior cingulate and insular cortices on anxiogenic-like responses induced by empathy for pain.

Mice cohabiting with a conspecific in chronic pain display anxiogenesis in the elevated plus-maze (EPM). Given that the anterior cingulate (ACC) and insular (InC) cortices play a role in the modulation of anxiety, pain, and emotional contagion, we investigated (a) the FosB activation in both brain areas and (b) the effects of intra-ACC or -InC injection of cobalt chloride (CoCl2, a synaptic blocker), on the anxiety of mice cohabiting with a cagemate suffering pain. Twenty-one days after birth, male Swiss mice were housed in pairs for 14 days to establish familiarity. On the 14th day, mice were divided into two groups: cagemate sciatic nerve constriction (CNC; i.e., one animal of each pair was subjected to sciatic nerve constriction), and cagemate sham (CS; i.e., a similar procedure but without suffering nerve constriction). After that, both groups were housed again with the same pairs for the other 14 days. On the 28th day, mice had their brains removed for the immunoassays analyses (Exp. 1). For experiments 2 and 3, on the 23rd day, the cagemates received guide cannula implantation bilaterally in the ACC or InC and, on the 28th day, they received local injections of saline or CoCl2, and then were exposed to the EPM. Results showed that cohabitation with a conspecific with chronic pain decreases and increases neuronal activation (FosB) within the ACC and InC, respectively. Intra-ACC or InC injection of CoCl2 reversed the anxiogenic effect in those animals that cohabited with a conspecific in chronic pain. ACC and InC seem to modulate anxiety induced by emotional contagion in animals cohabitating with a conspecific suffering pain.

Late Frontal Negativity Discriminates Outcomes and Intentions in Trust-Repayment Behavior.

Altruism (a costly action that benefits others) and reciprocity (the repayment of acts in kind) differ in that the former expresses preferences about the outcome of a social interaction, whereas the latter requires, in addition, ascribing intentions to others. Interestingly, an individual's behavior and neurophysiological activity under outcome- versus intention-based interactions has not been compared directly using different endowments in the same subject and during the same session. Here, we used a mixed version of the Dictator and the Investment games, together with electroencephalography, to uncover a subject's behavior and brain activity when challenged with endowments of different sizes in contexts that call for an altruistic (outcome-based) versus a reciprocal (intention-based) response. We found that subjects displayed positive or negative reciprocity (reciprocal responses greater or smaller than that for altruism, respectively) depending on the amount of trust they received. Furthermore, a subject's late frontal negativity differed between conditions, predicting responses to trust in intentions-based trials. Finally, brain regions related with mentalizing and cognitive control were the cortical sources of this activity. Thus, our work disentangles the behavioral components present in the repayment of trust, and sheds light on the neural activity underlying the integration of outcomes and perceived intentions in human economic interactions.

Alterações do córtex cingulado anterior como um preditor de resposta à terapia cognitivo-comportamental / Alterations of anterior cingulate cortex as predictors of response to cognitive-behavioral therapy

RESUMO Objetivo A terapia cognitivo-comportamental (TCC) tem eficácia bem-documentada na literatura científica para transtornos relacionados aos sintomas da ansiedade. No entanto, há uma parcela de pacientes que não responde ao tratamento psicoterápico. Por isso, os estudos sobre as alterações no córtex cingulado anterior (CCA) como preditoras neurais do tratamento têm contribuído para encontrar respostas sobre as diferenças nas respostas ao tratamento. O objetivo do presente estudo é descrever, por meio de revisão sistemática, os estudos encontrados até o ano de 2018 sobre o papel do CCA na predição de resposta à terapia. Métodos Foram realizadas buscas nas bases PsycInfo, Web of Science e PubMed com termos referentes ao tema "córtex cingulado anterior", "terapia cognitivo-comportamental" e "predição de respostas", incluindo estudos com neuroimagem estrutural e funcional. Resultados As buscas apresentaram 14 artigos sobre "transtorno de estresse pós-traumático (TEPT)", "transtorno obsessivo-compulsivo (TOC)" e "transtorno de ansiedade social (TAS)". Os estudos com neuroimagem estrutural apresentaram resultados promissores. A maior espessura do CCA foi preditora de melhor resposta ao tratamento para TEPT e TOC. Os resultados de neuroimagem funcional foram promissores para maior ativação como preditora de melhor resposta para TAS. Por outro lado, os resultados para TEPT apontaram que a menor ativação pode ser preditora de melhores respostas. Conclusão As alterações nos estudos de neuroimagem sugerem que o CCA tenha um papel de predição de resposta ao tratamento com TCC. Estudos posteriores com amostras maiores podem contribuir para a ampliação da eficácia nos tratamentos de tais transtornos.

ABSTRACT Objective The efficacy of cognitive-behavioral therapy (CBT) on the treatment of anxiety-related disorders has been well documented. However, a number of patients do not respond to psychotherapeutic treatment. Therefore, changes in the anterior cingulate cortex (ACC) as a neural predictor of treatment response have contributed to understanding the differences in treatment outcome. The aim of this study is to describe, through a systematic review, studies published until 2018 that investigate the role of the anterior cingulate cortex on the prediction of response to therapy. Methods Searches have been conducted in the PsycInfo, Web of Science and PubMed databases for articles related to the terms "anterior cingulate cortex", "cognitive-behavioral therapy" and "prediction of response", including studies with structural and functional neuroimaging. Results We selected 14 articles on "post-traumatic stress disorder (PTSD)", "obsessive-compulsive disorder (OCD)" and "social anxiety disorder (SAD)". Overall, Structural neuroimaging studies functional neuroimaging results were promising. A greater thickness on the ACC was associated with a better response to treatment for PTSD and OCD. Greater activation of the ACC was positively associated with a greater response to treatment for patients with SAD. On the other hand, for those with PTSD, lower activation may be a better predictor of improvement. Conclusion The structural and functional alterations observed in neuroimage studies suggest that the ACC has a role in predicting treatment response to CBT. Future studies with larger samples may contribute to the improvement of treatment efficacy in such disorders.

An MRI Study of the Metabolic and Structural Abnormalities in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric illness characterized by obsessions and/or compulsions. Its pathophysiology is still not well understood but it is known that the cortico-striatal-thalamic-cortical (CSTC) circuitry plays an important role. Here, we used a multi-method MRI approach combining proton magnetic resonance spectroscopy (H1-MRS) and diffusion tensor imaging (DTI) techniques to investigate both the metabolic and the microstructural white matter (WM) changes of the anterior cingulate cortex (ACC) in OCD patients as compared to healthy controls. Twenty-three OCD patients and 21 age-, sex-, and education-matched healthy volunteers participated in the study. Our 1H-MRS findings show increased levels of Glx in ACC in OCD. Further, significantly lower fractional anisotropy (FA) values were observed in OCD patients' left cingulate bundle (CB) as compared to healthy controls. Finally, there was a negative correlation between FA in the left CB and level of obsessions, as well as the duration of the illness. Our findings reinforce the involvement of CSTC bundles in pathophysiology of OCD, pointing to a specific role of glutamate (glutamine) and WM integrity.

Hippocampal plasticity mechanisms mediating experience-dependent learning change over time.

The requirement of NMDA receptor (NMDAR) activity for memory formation is well described. However, the plasticity mechanisms for memory can be modified by experience, such that a future similar learning becomes independent of NMDARs. This effect has often been reported in learning events conducted with a few days interval. In this work, we asked whether the NMDAR-independency is permanent or the brain regions and plasticity mechanisms of experience-dependent learning may change over time. Considering that contextual memories undergo a gradual reorganization over time, becoming progressively independent from the hippocampus and dependent upon cortical regions, we investigated the brain regions mediating a new related learning conducted at a remote time-point, when the first memory was already cortically established. First, we demonstrated that anterior cingulate cortex was not able to support a learning subsequent to a previous systems-level consolidated memory; it did require at least one functional subregion of the hippocampus (ventral or dorsal). Moreover, after replicating findings showing that a few days interval between trainings induces a NMDAR-independent learning, we managed to show that a learning following a longer interval once again becomes dependent on NMDARs in the hippocampus. These findings suggest that while the previous memory grows independent from the hippocampus over time, an experience-dependent learning following a systems-consolidated memory once again engages the hippocampus and a NMDAR-dependent plasticity mechanism.

Differential Effects of Inactivation of Discrete Regions of Medial Prefrontal Cortex on Memory Consolidation of Moderate and Intense Inhibitory Avoidance Training.

It has been found that the medial prefrontal cortex (mPFC) is involved in memory encoding of aversive events, such as inhibitory avoidance (IA) training. Dissociable roles have been described for different mPFC subregions regarding various memory processes, wherein the anterior cingulate cortex (ACC), prelimbic cortex (PL), and infralimbic cortex (IL) are involved in acquisition, retrieval, and extinction of aversive events, respectively. On the other hand, it has been demonstrated that intense training impedes the effects on memory of treatments that typically interfere with memory consolidation. The aim of this work was to determine if there are differential effects on memory induced by reversible inactivation of neural activity of ACC, PL, or IL produced by tetrodotoxin (TTX) in rats trained in IA using moderate (1.0 mA) and intense (3.0 mA) foot-shocks. We found that inactivation of ACC has no effects on memory consolidation, regardless of intensity of training. PL inactivation impairs memory consolidation in the 1.0 mA group, while no effect on consolidation was produced in the 3.0 mA group. In the case of IL, a remarkable amnestic effect in LTM was observed in both training conditions. However, state-dependency can explain the amnestic effect of TTX found in the 3.0 mA IL group. In order to circumvent this effect, TTX was injected into IL immediately after training (thus avoiding state-dependency). The behavioral results are equivalent to those found after PL inactivation. Therefore, these findings provide evidence that PL and IL, but not ACC, mediate LTM of IA only in moderate training.

Decrease in NMDA receptor-signalling activity in the anterior cingulate cortex diminishes defensive behaviour and unconditioned fear-induced antinociception elicited by GABAergic tonic inhibition impairment in the posterior hypothalamus.

Acute γ-aminobutyric acid (GABA) disinhibition in the posterior hypothalamus (PH) elicits defensive reactions that are considered anxiety- and panic attack-like behaviour, and these defensive reactions are followed by antinociception. Evidence indicates that the PH connects with the medial prefrontal cortex, particularly the anterior cingulate cortex (ACC), which seems to regulate these unconditioned fear-induced defensive responses. However, few studies have shown the participation of cortical regions in the control of behavioural and antinociceptive responses organised by diencephalic structures. It has been suggested that the glutamatergic system can mediate this cortical influence, as excitatory imbalance is believed to play a role in both defensive mechanisms. Thus, the aim of the present study was to investigate the involvement of ACC glutamatergic connections via blockade of local N-methyl-D-aspartate (NMDA) receptors to elaborate panic-like defensive behaviours and unconditioned fear-induced antinociception organised by PH neurons. Wistar rats were treated with microinjections of 0.9% NaCl or LY235959 (a selective NMDA receptor antagonist) in the ACC at different concentrations (2, 4 and 8 nmol/0.2µL), followed by GABAA receptor blockade in the PH. Defensive reactions were analysed for 20min, and the nociceptive threshold was then measured at 10-min intervals for 60min. Pretreatment of the ACC with LY235959 reduced both panic-like defensive behaviour and fear-induced antinociception evoked by PH GABAergic disinhibition. Our findings suggest that ACC NMDA receptor-signalled glutamatergic inputs play a relevant role in the organisation of anxiety- and panic attack-like behaviours and in fear-induced antinociception.

Electrophysiological Evidence That the Retrosplenial Cortex Displays a Strong and Specific Activation Phased with Hippocampal Theta during Paradoxical (REM) Sleep.

It is widely accepted that cortical neurons are similarly more activated during waking and paradoxical sleep (PS; aka REM) than during slow-wave sleep (SWS). However, we recently reported using Fos labeling that only a few limbic cortical structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) contain a large number of neurons activated during PS hypersomnia. Our aim in the present study was to record local field potentials and unit activity from these two structures across all vigilance states in freely moving male rats to determine whether the RSC and the ACA are electrophysiologically specifically active during basal PS episodes. We found that theta power was significantly higher during PS than during active waking (aWK) similarly in the RSC and hippocampus (HPC) but not in ACA. Phase-amplitude coupling between HPC theta and gamma oscillations strongly and specifically increased in RSC during PS compared with aWK. It did not occur in ACA. Further, 68% and 43% of the units recorded in the RSC and ACA were significantly more active during PS than during aWK and SWS, respectively. In addition, neuronal discharge of RSC but not of ACA neurons increased just after the peak of hippocampal theta wave. Our results show for the first time that RSC neurons display enhanced spiking in synchrony with theta specifically during PS. We propose that activation of RSC neurons specifically during PS may play a role in the offline consolidation of spatial memories, and in the generation of vivid perceptual scenery during dreaming.SIGNIFICANCE STATEMENT Fifty years ago, Michel Jouvet used the term paradoxical to define REM sleep because of the simultaneous occurrence of a cortical activation similar to waking accompanied by muscle atonia. However, we recently demonstrated using functional neuroanatomy that only a few limbic structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) are activated during PS. In the present study, we show for the first time that the RSC and ACA contain neurons firing more during PS than in any other state. Further, RSC neurons are firing in phase with the hippocampal theta rhythm. These data indicate that the RSC is very active during PS and could play a key role in memory consolidation taking place during this state.