Activity In Basolateral Amygdala Research Articles

Pathways to adolescent social anxiety: Testing interactions between neural social reward function and perceived social threat in daily life.

Recent theories suggest that for youth highly sensitive to incentives, perceiving more social threat may contribute to social anxiety (SA) symptoms. In 129 girls (ages 11-13) oversampled for shy/fearful temperament, we thus examined how interactions between neural responses to social reward (vs. neutral) cues (measured during anticipation of peer feedback) and perceived social threat in daily peer interactions (measured using ecological momentary assessment) predict SA symptoms two years later. No significant interactions emerged when neural reward function was modeled as a latent factor. Secondary analyses showed that higher perceived social threat was associated with more severe SA symptoms two years later only for girls with higher basolateral amygdala (BLA) activation to social reward cues at baseline. Interaction effects were specific to BLA activation to social reward (not threat) cues, though a main effect of BLA activation to social threat (vs. neutral) cues on SA emerged. Unexpectedly, interactions between social threat and BLA activation to social reward cues also predicted generalized anxiety and depression symptoms two years later, suggesting possible transdiagnostic risk pathways. Perceiving high social threat may be particularly detrimental for youth highly sensitive to reward incentives, potentially due to mediating reward learning processes, though this remains to be tested.

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).

Dopamine projections to the basolateral amygdala drive the encoding of identity-specific reward memories.

To make adaptive decisions, we build an internal model of the associative relationships in an environment and use it to make predictions and inferences about specific available outcomes. Detailed, identity-specific cue-reward memories are a core feature of such cognitive maps. Here we used fiber photometry, cell-type and pathway-specific optogenetic manipulation, Pavlovian cue-reward conditioning and decision-making tests in male and female rats, to reveal that ventral tegmental area dopamine (VTADA) projections to the basolateral amygdala (BLA) drive the encoding of identity-specific cue-reward memories. Dopamine is released in the BLA during cue-reward pairing; VTADA→BLA activity is necessary and sufficient to link the identifying features of a reward to a predictive cue but does not assign general incentive properties to the cue or mediate reinforcement. These data reveal a dopaminergic pathway for the learning that supports adaptive decision-making and help explain how VTADA neurons achieve their emerging multifaceted role in learning.

Anterior and Posterior Basolateral Amygdala Projections of Cell Type–Specific D1-Expressing Neurons From the Medial Prefrontal Cortex Differentially Control Alcohol-Seeking Behavior

BackgroundAlcohol use disorder is characterized by compulsive alcohol-seeking behavior, which is associated with dysregulation of afferent projections from the medial prefrontal cortex to the basolateral amygdala (BLA). However, the contribution of the cell type–specific mechanism in this neuronal circuit to alcohol-seeking behavior remains unclear. MethodsMice were trained with 2-bottle choice and operant alcohol self-administration procedures. Anterograde and retrograde viral methods traced the connection between dopamine type 1 receptor (D1R) neurons and BLA neurons. Electrophysiology and in vivo optogenetic techniques were used to test the function of neural circuits in alcohol-seeking behavior. ResultsChronic alcohol consumption preferentially changed the activity of posterior BLA (pBLA) neurons but not anterior BLA (aBLA) neurons and overexcited D1R neurons in the medial prefrontal cortex. Interestingly, we found that 2 populations of D1R neurons, anterior and posterior (pD1R) neurons, separately targeted the aBLA and pBLA, respectively, and only a few D1R neurons innervated both aBLA and pBLA neurons. Furthermore, pD1R neurons exhibited more excitability than anterior D1R neurons in alcohol-drinking mice. Moreover, we observed enhanced glutamatergic transmission and an increased NMDA/AMPA receptor ratio in the medial prefrontal cortex inputs from pD1R neurons to the pBLA. Optogenetic long-term depression induction of the pD1R-pBLA circuit reduced alcohol-seeking behavior, while optogenetic long-term depression or long-term potentiation induction of the anterior D1R–aBLA circuit produced no change in alcohol intake. ConclusionsThe pD1R-pBLA circuit mediates chronic alcohol consumption, which may suggest a cell type–specific neuronal mechanism underlying reward-seeking behavior in alcohol use disorder.

Cholecystokinin B receptor antagonists for the treatment of depression via blocking long-term potentiation in the basolateral amygdala.

Depression is a common and severe mental disorder. Evidence suggested a substantial causal relationship between stressful life events and the onset of episodes of major depression. However, the stress-induced pathogenesis of depression and the related neural circuitry is poorly understood. Here, we investigated how cholecystokinin (CCK) and CCKBR in the basolateral amygdala (BLA) are implicated in stress-mediated depressive-like behavior. The BLA mediates emotional memories, and long-term potentiation (LTP) is widely considered a trace of memory. We identified that the cholecystokinin knockout (CCK-KO) mice impaired LTP in the BLA, while the application of CCK4 induced LTP after low-frequency stimulation (LFS). The entorhinal cortex (EC) CCK neurons project to the BLA and optogenetic activation of EC CCK afferents to BLA-promoted stress susceptibility through the release of CCK. We demonstrated that EC CCK neurons innervate CCKBR cells in the BLA and CCK-B receptor knockout (CCKBR-KO) mice impaired LTP in the BLA. Moreover, the CCKBR antagonists also blocked high-frequency stimulation (HFS) induced LTP formation in the BLA. Notably, CCKBR antagonists infusion into the BLA displayed an antidepressant-like effect in the chronic social defeat stress model. Together, these results indicate that CCKBR could be a potential target to treat depression.

0073 Investigating the epigenetic mechanisms underlying memory consolidation during sleep

Abstract Introduction It has been established that sleep after learning something (“post-learning sleep”) actively consolidates what was learned. Yet, the underlying cellular and molecular mechanisms are undergoing active investigation. The fear conditioning (FC) memory paradigm, in which an animal learns to associate an environmental cue to an aversive foot shock, has been widely used for memory investigation. While amygdala and hippocampus are two critical sites for processing and storing the FC memory, how the amygdala consolidate this memory during sleep, from both cellular and molecular perspectives, has been little understood, compared to the hippocampus. Moreover, one potential molecular substrate of memory, DNA methylation, has been studied in the hippocampus for its role in learning and memory. Yet it is little known for its memory role in the BLA. Methods Here, we used fiber photometry, miniscope calcium imaging, EEG recording, optogenetic manipulation, and whole genome bisulfite sequencing to study the neural mechanisms underlying memory consolidation in the basolateral amygdala (BLA) during sleep. Results (1) We found that the BLA neurons display increased activity during REM sleep, compared to that in non-REM (NREM) sleep. (2) Using closed-loop optogenetic strategy, our preliminary results showed that silencing BLA activity during REM sleep leads to memory impairment in contextual fear conditioning task. (3) We compared DNA methylation of BLA neurons at a whole genome level between mice with and without sleep after FC learning and identified differentially methylated regions between them. Conclusion Together, our data suggests that the BLA activity during REM sleep is required for consolidation of fear memory, and DNA methylation might mediate this process. Support (if any)

Marco Capogna, a pioneering neuroscientist and true European

Marco Capogna, a pioneering neuroscientist and true European

Maturation of a cortical-amygdala circuit limits sociability in male rats.

Prefrontal cortical maturation coincides with adolescent transitions in social engagement, suggesting that it influences social development. The anterior cingulate cortex (ACC) is important for social interaction, including ACC outputs to the basolateral amygdala (BLA). However, little is known about ACC-BLA sensitivity to the social environment and if this changes during maturation. Here, we used brief (2-hour) isolation to test the immediate impact of changing the social environment on the ACC-BLA circuit and subsequent shifts in social behavior of adolescent and adult rats. We found that optogenetic inhibition of the ACC during brief isolation reduced isolation-driven facilitation of social interaction across ages. Isolation increased activity of ACC-BLA neurons across ages, but altered the influence of ACC on BLA activity in an age-dependent manner. Isolation reduced the inhibitory impact of ACC stimulation on BLA neurons in a frequency-dependent manner in adults, but uniformly suppressed ACC-driven BLA activity in adolescents. This work identifies isolation-driven alterations in an ACC-BLA circuit, and the ACC itself as an essential region sensitive to social environment and regulates its impact on social behavior in both adults and adolescents.

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress

BackgroundThe “missing” link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice.MethodsMale C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed.ResultsMice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS–IFI16–STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors.ConclusionsOur results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.

Increased basolateral amygdala metabolic activity during flavor familiarization: an experimental study

BackgroundNovel flavors elicit a cautious neophobic response which is attenuated as the flavor becomes familiar and safe. The attenuation of neophobia reveals the formation of a safe memory. Previous lesion studies in rats have reported that basolateral amygdala integrity is required for taste neophobia, but not neophobia to flavor, i.e., taste linked to an odorous component. Accordingly, immunohistochemical analyses show that novel tastes induced higher basolateral amygdala activity when compared to familiar ones. However, a different role of basolateral amygdala in flavor attenuation of neophobia is suggested by lesion studies using a vinegar solution. Studies assessing basolateral amygdala activity during flavor attenuation of neophobia are lacking. Thus, we quantified cytochrome oxidase as an index of basolateral amygdala activity along the first and second vinegar exposures in order to assess flavor neophobia and attenuation of neophobia.MethodsWe exposed adult male Wistar rats either once or twice to a 3% cider vinegar solution or water, and compared the basolateral amygdala, piriform cortex and caudate putamen brain metabolic activity using cytochrome c-oxidase histochemistry.ResultsWe found increased flavor intake and cytochrome c-oxidase histochemistry activity during the second exposure in basolateral amygdala, but not in the piriform cortex and caudate/putamen.ConclusionsThe main finding of the study is that BLA metabolic activity was higher in the group exposed to a familiar vinegar solution than in the groups exposed to either water or a novel vinegar solution.

Liposaccharide-induced sustained mild inflammation fragments social behavior and alters basolateral amygdala activity.

Conditions with sustained low-grade inflammation have high comorbidity with depression and anxiety and are associated with social withdrawal. The basolateral amygdala (BLA) is critical for affective and social behaviors and is sensitive to inflammatory challenges. Large systemic doses of lipopolysaccharide (LPS) initiate peripheral inflammation, increase BLA neuronal activity, and disrupt social and affective measures in rodents. However, LPS doses commonly used in behavioral studies are high enough to evoke sickness syndrome, which can confound interpretation of amygdala-associated behaviors. The objectives of this study were to find a LPS dose that triggers mild peripheral inflammation but not observable sickness syndrome in adult male rats, to test the effects of sustained mild inflammation on BLA and social behaviors. To accomplish this, we administered single doses of LPS (0-100μg/kg, intraperitoneally) and measured open field behavior, or repeated LPS (5μg/kg, 3 consecutive days), and measured BLA neuronal firing, social interaction, and elevated plus maze behavior. Repeated low-dose LPS decreased BLA neuron firing rate but increased the total number of active BLA neurons. Repeated low-dose LPS also caused early disengagement during social bouts and less anogenital investigation and an overall pattern of heightened social caution associated with reduced gain of social familiarity over the course of a social session. These results provide evidence for parallel shifts in social interaction and amygdala activity caused by prolonged mild inflammation. This effect of inflammation may contribute to social symptoms associated with comorbid depression and chronic inflammatory conditions.

Activation of basolateral amygdala to anterior cingulate cortex circuit alleviates MK-801 induced social and cognitive deficits of schizophrenia.

Schizophrenia is a severe psychiatric disorder with a high prevalence worldwide, however, its pathogenesis remains poorly understood. In this study, we used the non-competitive NMDA receptor antagonist MK-801 to induce schizophrenia-like behaviors and confirmed that mice exhibited stereotypic rotational behavior and hyperlocomotion, social interaction defects and cognitive dysfunction, similar to the clinical symptoms in patients. Here, the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) were involved in the schizophrenia-like behaviors induced by MK-801. Furthermore, we confirmed BLA sent glutamatergic projection to the ACC. Chemogenetic and optogenetic regulation of BLA-ACC projecting neurons affected social and cognitive deficits but not stereotypic rotational behavior in MK-801-treated mice. Overall, our study revealed that the BLA-ACC circuit plays a major role and may be a potential target for treating schizophrenia-related symptoms.

Effects of treadmill exercise and chronic stress on anxiety-like behavior, neuronal activity, and oxidative stress in basolateral amygdala in morphine-treated rats.

The basolateral amygdala (BLA), which is sensitive to stress, is necessary for reward-seeking behavior and addiction. Regular exercise can produce various positive effects by affecting the BLA. Therefore, we aimed to investigate the effects of chronic stress and treadmill running (TR) on anxiety-like behavior, neuronal activity, lipid peroxidation (measured by malondialdehyde (MDA) levels, a marker foroxidative stress), and total thiol in BLA, in morphine-treated rats. Male Wistar rats were restricted in restraint stress and/or ran on the treadmill and treated with morphine (5 mg/kg) for 21 days. Anxiety-like behavior was evaluated using an elevated plus maze (EPM) and open field tests (OFTs), on day 22. On day 23, neuronal activity in BLA was assessed via single-unit recording. Finally, MDA and total thiol were assessed in BLA. Our results showed that chronic administration of morphine (5 mg/kg) did not affect anxiety-like behavior. However, the morphine-treated rats, subjected to chronic stress and exercise, showed fewer anxiety-like behaviors. Morphine increased BLA's MDA levels but it was prevented by TR. Glutamatergic and GABAergic basal neuronal activities were low in morphine-treated rats but after acute morphine application, there was a significant decrease in GABAergic neuronal activities in the morphine-exercise-stress (Mor-Exe-St) group. The results of this study showed that in morphine-treated rats, stress and exercise or their combination could have either co-directional or opposite effects to the chronic effects of morphine. These results indicate the existence of common pathways similar to endogenous opioids.

ACh signaling modulates activity of the GABAergic signaling network in the basolateral amygdala and behavior in stress-relevant paradigms.

The balance between excitatory and inhibitory (E/I) signaling is important for maintaining homeostatic function in the brain. Indeed, dysregulation of inhibitory GABA interneurons in the amygdala has been implicated in human mood disorders. We hypothesized that acetylcholine (ACh) signaling in the basolateral amygdala (BLA) might alter E/I balance resulting in changes in stress-sensitive behaviors. We therefore measured ACh release as well as activity of calmodulin-dependent protein kinase II (CAMKII)-, parvalbumin (PV)-, somatostatin (SOM)- and vasoactive intestinal protein (VIP)-expressing neurons in the BLA of awake, behaving male mice. ACh levels and activity of both excitatory and inhibitory BLA neurons increased when animals were actively coping, and decreased during passive coping, in the light-dark box, tail suspension and social defeat. Changes in neuronal activity preceded behavioral state transitions, suggesting that BLA activity may drive the shift in coping strategy. In contrast to exposure to escapable stressors, prolonging ACh signaling with a cholinesterase antagonist changed the balance of activity among BLA cell types, significantly increasing activity of VIP neurons and decreasing activity of SOM cells, with little effect on CaMKII or PV neurons. Knockdown of α7 or β2-containing nAChR subtypes in PV and SOM, but not CaMKII or VIP, BLA neurons altered behavioral responses to stressors, suggesting that ACh signaling through nAChRs on GABA neuron subtypes contributes to stress-induced changes in behavior. These studies show that ACh modulates the GABAergic signaling network in the BLA, shifting the balance between SOM, PV, VIP and CaMKII neurons, which are normally activated coordinately during active coping in response to stress. Thus, prolonging ACh signaling, as occurs in response to chronic stress, may contribute to maladaptive behaviors by shifting the balance of inhibitory signaling in the BLA.

Longitudinal assessment of amygdala activity in mice susceptible to trauma

Resilience to consequences of trauma exposure contains relevant information about the processes that contribute to the maintenance of mental health in the face of adversity; information that is essential to improve treatment success of stress-related mental diseases. Prior literature has implicated aberrant amygdala (re)activity as potential factor contributing to trauma susceptibility. However, it remains to be resolved which amygdalar subregions and neuronal subclasses are involved, and when – i.e., pre-, peri- or post-trauma exposure – and under what conditions changes in amygdala (re)activity manifest themselves. Here, we implemented a preclinical rodent model for PTSD that entailed exposure to a traumatic event (severe, unpredictable foot shock) followed by a trigger (mild, predictable foot shock). Using behavioral phenotyping, trauma susceptible vs. resilient mice were identified and pre-, peri- or post-trauma amygdala activity was compared. Neuronal activity was tagged in living mice by the use of the ArcTRAP transgenic mouse line, labeling all activated (i.e., Arc-expressing) neurons by a systemic injection of tamoxifen. Furthermore, we assessed amygdala responses during fear memory recall, induced by either (re-)exposure to the trauma, trigger, or a novel, yet similar context, and analyzed behavioral fear responses under these conditions, as well as basal anxiety in the mice. Results revealed no major differences dissociating susceptible vs. resilient mice prior to trauma exposure, but exaggerated activity in specifically the basolateral amygdala (BLA) peri-trauma that predicted susceptibility to later PTSD-like symptoms. Post-trauma, susceptible mice did not display altered basal amygdala activity, but BLA hyperreactivity in response to trigger context re-exposure, and BLA hyporesponsivity in response to the trauma context. Exposure to the novel, similar context evoked a differential temporal pattern of freezing behavior in susceptible mice and an increased activity of amygdalar somatostatin-expressing neurons specifically. As such, these results for the first time show that deviant BLA activity during fear learning predicts susceptibility to its long-term consequences and that aberrant subsequent BLA responses to stressful contexts depend on the exact context.

Social status mediates behavioral, endocrine, and neural responses to an intruder challenge in a social cichlid, Astatotilapia burtoni

Most animals encounter social challenges throughout their lives as they compete for resources. Individual responses to such challenges can depend on social status, sex, and community-level attributes, yet most of our knowledge of the behavioral and physiological mechanisms by which individuals respond to challenges has come from dyadic interactions between a resource holder and a challenger (usually both males). To incorporate differences in individual behavior that are influenced by surrounding group members, we use naturalistic communities of the cichlid fish, Astatotilapia burtoni, and examine resident dominant male responses to a territorial intrusion within the social group. We measured behavior and steroid hormones (testosterone and cortisol), and neural activity in key brain regions implicated in regulating territorial and social dominance behavior. In response to a male intruder, resident dominant males shifted from border defense to overt attack behavior, accompanied by decreased basolateral amygdala activity. These differences were context dependent – resident dominant males only exhibited increased border defense when the intruder secured dominance. Neither subordinate males nor females changed their behavior in response to a territorial intrusion in their community. However, neural activity in both hippocampus and lateral septum of subordinates increased when the intruder failed to establish dominance. Our results demonstrate how a social challenge results in multi-faceted behavioral, hormonal, and neural changes, depending on social status, sex, and the outcome of an intruder challenge. Taken together, our work provides novel insights into the mechanisms through which individual group members display context- and status-appropriate challenge responses in dynamic social groups.

Contingent Amygdala Inputs Trigger Heterosynaptic LTP at Hippocampus-To-Accumbens Synapses.

The nucleus accumbens shell (NAcSh) is a key brain region where environmental cues acquire incentive salience to reinforce motivated behaviors. Principal medium spiny neurons (MSNs) in the NAcSh receive extensive glutamatergic projections from limbic regions, among which, the ventral hippocampus (vH) transmits information enriched in contextual cues, and the basolateral amygdala (BLA) encodes real-time arousing states. The vH and BLA project convergently to NAcSh MSNs, both activated in a time-locked manner on a cue-conditioned motivational action. In brain slices prepared from male and female mice, we show that co-activation of the two projections induces long-term potentiation (LTP) at vH-to-NAcSh synapses without affecting BLA-to-NAcSh synapses, revealing a heterosynaptic mechanism through which BLA signals persistently increase the temporally contingent vH-to-NAcSh transmission. Furthermore, this LTP is more prominent in dopamine D1 receptor-expressing (D1) MSNs than D2 MSNs and can be prevented by inhibition of either D1 receptors or dopaminergic terminals in NAcSh. This heterosynaptic LTP may provide a dopamine-guided mechanism through which vH-encoded cue inputs that are contingent to BLA activation acquire increased circuit representation to reinforce behavior.SIGNIFICANCE STATEMENT In motivated behaviors, environmental cues associated with arousing stimuli acquire increased incentive salience, processes mediated in part by the nucleus accumbens (NAc). NAc principal neurons receive glutamatergic projections from the ventral hippocampus (vH) and basolateral amygdala (BLA), which transmit information encoding contextual cues and affective states, respectively. Our results show that co-activation of the two projections induces long-term potentiation (LTP) at vH-to-NAc synapses without affecting BLA-to-NAc synapses, revealing a heterosynaptic mechanism through which BLA signals potentiate the temporally contingent vH-to-NAc transmission. Furthermore, this LTP is prevented by inhibition of either D1 receptors or dopaminergic axons. This heterosynaptic LTP may provide a dopamine-guided mechanism through which vH-encoded cue inputs that are contingent to BLA activation acquire increased circuit representation to reinforce behavior.

Inhibition of Glycogen Synthase Kinase 3β Activity in the Basolateral Amygdala Disrupts Reconsolidation and Attenuates Heroin Relapse.

Exposure to a heroin-associated conditioned stimulus can reactivate drug reward memory, trigger drug cravings, and induce relapse in heroin addicts. The amygdala, a brain region related to emotions and motivation, is involved in processing rewarding stimulus. Recent evidence demonstrated that disrupting the reconsolidation of the heroin drug memories attenuated heroin seeking which was associated with the basolateral amygdala (BLA). Meanwhile, neural functions associated with learning and memory, like synaptic plasticity, are regulated by glycogen synthase kinase 3 beta (GSK-3β). In addition, GSK-3β regulated memory processes, like retrieval and reconsolidation of cocaine-induced memory. Here, we used a heroin intravenous self-administration (SA) paradigm to illustrate the potential role of GSK-3β in the reconsolidation of drug memory. Therefore, we used SB216763 as a selective inhibitor of GSK-3β. We found that injecting the selective inhibitor SB216763 into the BLA, but not the central amygdala (CeA), immediately after heroin-induced memory retrieval disrupted reconsolidation of heroin drug memory and significantly attenuated heroin-seeking behavior in subsequent drug-primed reinstatement, suggesting that GSK-3β is critical for reconsolidation of heroin drug memories and inhibiting the activity of GSK-3β in BLA disrupted heroin drug memory and reduced relapse. However, no retrieval or 6 h after retrieval, administration of SB216763 into the BLA did not alter heroin-seeking behavior in subsequent heroin-primed reinstatement, suggesting that GSK-3β activity is retrieval-dependent and time-specific. More importantly, a long-term effect of SB216763 treatment was observed in a detectable decrease in heroin-seeking behavior, which lasted at least 28 days. All in all, this present study demonstrates that the activity of GSK-3β in BLA is required for reconsolidation of heroin drug memory, and inhibiting GSK-3β activity of BLA disrupts reconsolidation and attenuates heroin relapse.

Sleep deprivation altered encoding of basolateral amygdala on fear acquisition.

Sleep deprivation (SD) may lead to the development of fear- and anxiety-related emotional disorders. However, the neural mechanisms underlying the effects of SD on fear acquisition are unclear. Here, we tested whether and how SD influences the behavioral and neural manifestations of fear acquisition. We found that subjective fear ratings and objective fear indices (skin conductance response [SCR]) in the SD group were greater than those in the control group during fear acquisition, suggesting that SD facilitated fear acquisition (nSD = 18 and ncontrol = 23 for self-reported rating analysis; nSD = 10 and ncontrol = 10 for SCR analysis). Neuroimaging data showed that the SD group exhibited stronger activity in the left basolateral amygdala (BLA) and left superficial amygdala (SFA). Moreover, the left BLA activity, which positively correlated with the objective fear indices, significantly mediated the effect of SD on fear acquisition. Together, the present findings indicate that SD facilitates fear acquisition by augmenting threat-specific encoding in the BLA, which may be a potential biomarker of the risk of developing fear-related disorders under traumatic and distressing situations.

Basolateral amygdala activation enhances object recognition memory by inhibiting anterior insular cortex activity

Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.