Infralimbic Research Articles

Chronic social defeat alters behaviors and neuronal activation in the brain of female Mongolian gerbils

Chronic social defeat has been found to be stressful and to affect many aspects of the brain and behaviors in males. However, relatively little is known about its effects on females. In the present study, we examined the effects of repeated social defeat on social approach and anxiety-like behaviors as well as the neuronal activation in the brain of sexually naïve female Mongolian gerbils (Meriones unguiculatus). Our data indicate that repeated social defeats for 20 days reduced social approach and social investigation, but increased risk assessment or vigilance to an unfamiliar conspecific. Such social defeat experience also increased anxiety-like behavior and reduced locomotor activity. Using ΔFosB-immunoreactive (ΔFosB-ir) staining as a marker of neuronal activation in the brain, we found significant elevations by social defeat experience in the density of ΔFosB-ir stained neurons in several brain regions, including the prelimbic (PL) and infralimbic (IL) subnuclei of the prefrontal cortex (PFC), CA1 subfields (CA1) of the hippocampus, central subnuclei of the amygdala (CeA), the paraventricular nucleus (PVN), dorsomedial nucleus (DMH), and ventrolateral subdivision of the ventromedial nucleus (VMHvl) of the hypothalamus. As these brain regions have been implicated in social behaviors and stress responses, our data suggest that the specific patterns of neuronal activation in the brain may relate to the altered social and anxiety-like behaviors following chronic social defeat in female Mongolian gerbils.

The prelimbic cortex but not the anterior cingulate cortex plays an important role in social recognition and social investigation in mice.

The prefrontal cortex (PFC) has been implicated in social cognitive functions and emotional behaviors in rodents. Each subregion (prelimbic cortex, PL; infralimbic cortex; and anterior cingulate cortex, ACC) of the PFC appears to play a different role in social and emotional behaviors. However, previous investigations have produced inconsistent data, and few previous studies directly compared the roles of the PFC subregions using the same experimental paradigm. Accordingly, in the present study, we examined the role of the PL and the ACC in short-term social recognition, social investigation, and anxiety-related behaviors in C57BL/6J mice. We subjected mice with a lesioned PL or ACC, as well as those in a sham control group, to tests of social recognition and social novelty where juvenile and adult male mice were used as social stimuli. In the social recognition test, the PL-lesioned mice exhibited habituation but not dishabituation regardless of whether they encountered juvenile or adult mice. In a subsequent social novelty test, they spent less time engaged in social investigation compared with the control mice when adult mice were used as social stimuli. These results suggest that PL lesions impaired both social recognition and social investigation. In contrast, ACC-lesioned mice did not exhibit impaired short-term social recognition or social investigation regardless of the social stimulus. Furthermore, PL lesions and ACC lesions did not affect anxiety-related behavior in the open field test or light-dark transition test. Our findings demonstrate that the PL but not the ACC plays an important role in social recognition and social investigation.

Acceleration of GABA-switch after early life stress changes mouse prefrontal glutamatergic transmission

Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called “GABA-switch”.Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15–P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABAA receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development.

Involvement of cortical projections to basolateral amygdala in context-induced reinstatement of ethanol-seeking in rats

Ethanol is the most consumed substance of abuse in the world, and its misuse may lead to the development of alcohol use disorder (AUD). High relapse rates remain a relevant problem in the treatment of AUD. Exposure to environmental cues previously associated with ethanol intake could trigger ethanol-seeking behavior. However, the neural mechanisms involved in this phenomenon are not entirely clear. In this context, cortical projections to the basolateral amygdala (BLA) play a role in appetitive and aversive learned behaviors. Therefore, we aimed to evaluate the activation of the cortical projections from the prelimbic (PL), orbitofrontal (OFC), and infralimbic (IL), to the BLA in the context-induced reinstatement of ethanol-seeking. Male Long-Evans rats were trained to self-administer 10% ethanol in Context A. Subsequently, lever pressing in the presence of the discrete cue was extinguished in Context B. After nine extinction sessions, rats underwent intracranial surgery for the unilateral injection of red fluorescent retrograde tracer into the BLA. The context-induced reinstatement of ethanol-seeking was assessed by re-exposing the rats to Context A or B under extinction conditions. Finally, we combined retrograde neuronal tracing with Fos to identify activated cortical inputs to BLA during the reinstatement of ethanol-seeking behavior. We found that PL, but not OFC or IL, retrogradely-labeled neurons from BLA presented increased Fos expression during the re-exposure to the ethanol-associated context, suggesting that PL projection to BLA is involved in the context-induced reinstatement of ethanol-seeking behavior.

Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.

Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning. All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus. The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning. Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

Prefrontal representation of affective stimuli: importance of stress, sex, and context.

Stress-related disorders such as depression and anxiety exhibit sex differences in prevalence and negatively impact both mental and physical health. Affective illness is also frequently accompanied by changes in ventromedial prefrontal cortical (vmPFC) function. However, the neurobiology that underlies sex-specific cortical processing of affective stimuli is poorly understood. Although rodent studies have investigated the prefrontal impact of chronic stress, postmortem studies have focused largely on males and yielded mixed results. Therefore, genetically defined population recordings in behaving animals of both sexes were used to test the hypothesis that chronic variable stress (CVS) impairs the neural processing of affective stimuli in the rodent infralimbic region. Here, we targeted expression of a calcium indicator, GCaMP6s, to infralimbic pyramidal cells. In males, CVS reduced infralimbic responses to social interaction and restraint stress but increased responses to novel objects and food reward. In contrast, females did not have CVS-induced changes in infralimbic activity, which was partially dependent on the ovarian status. These results indicate that both male and female vmPFC cells encode social, stress, and reward stimuli. However, chronic stress effects are sex-dependent and behavior-specific. Ultimately, these findings extend the understanding of chronic stress-induced prefrontal dysfunction and indicate that sex is a critical factor for cortical processing of affective stimuli.

Glucocorticoid- β-adrenoceptors interactions in the infralimbic cortex in acquisition and consolidation of auditory fear memory extinction in rats

This study investigated the interactive effect of glucocorticoid and β-adrenoceptors in the infralimbic (IL) cortex on the acquisition and consolidation of fear extinction in rats' auditory fear conditioning (AFC) task. On day 1, rats underwent habituation for 9 min (12 tones, 10 s, 4 kHz, 80 dB, without footshock). On day 2 (conditioning), rats received 3 mild electrical footshocks (US; 2 s, 0.5 mA) paired with the auditory-conditioned stimulus (CS; tone: 30 s, 4 kHz, 80 dB). On days 3–5 (Ext 1–3), rats received 15 tones with no footshock in the test box. Intra-IL injection of corticosterone (CORT, 20 ng/0.5 μl per side) before Ext 1 and after Ext 1–2, respectively, facilitated the acquisition and consolidation of fear memory extinction. Intra-IL injection of the β2-adrenoceptor agonist clenbuterol (CLEN, 50 ng/0.5 μl per side) inhibited, but the β-adrenoceptor antagonist propranolol (PROP, 500 ng/0.5 μl per side) enhanced the facilitatory effects of CORT on fear memory extinction. CORT injection before the acquisition of fear extinction increased p-ERK levels in the IL. Co-injection of CORT with CLEN increased, but PROP decreased p-ERK activities. CORT injection after the consolidation of fear extinction increased p-CREB in the IL. Co-injection of CORT with CLEN increased, but PROP reduced p-CREB activities. Our findings show that corticosterone facilitates the acquisition and consolidation of fear memory extinction. GRs and β-adrenoceptors in the IL jointly regulate fear memory extinction via ERK and CREB signaling pathways. This pre-clinical animal study may highlight the effect of GRs and β-adrenoceptors of the IL cortex in regulating fear memory processes in fear-related disorders such as PTSD.

Poststress social isolation exerts anxiolytic effects by activating the ventral dentate gyrus

After aversive stress, people either choose to return to their previously familiar social environment or tend to adopt temporary social withdrawal to buffer negative emotions. However, which behavior intervention is more appropriate and when remain elusive. Here, we unexpectedly found that stressed mice experiencing social isolation exhibited less anxiety than those experiencing social contact. Within the first 24 h after returning to their previous social environment, mice experienced acute restraint stress (ARS) displayed low social interest but simultaneously received excessive social disturbance from their cage mates, indicating a critical time window for social isolation to balance the conflict. To screen brain regions that were differentially activated between the poststress social isolation and poststress social contact groups, we performed ΔFosB immunostaining and found that ΔFosB + signals were remarkably increased in the vDG of poststress social isolation group compared with poststress social contact group. There were no significant differences between the two groups in the other anxiety- and social-related brain regions, such as prelimbic cortex, infralimbic cortex, nucleus accumbens, etc. These data indicate that vDG is closely related to the differential phenotypes between the poststress social isolation and poststress social contact groups. Electrophysiological recording, further, revealed a higher activity of vDG in the poststress social isolation group than the poststress social contact group. Chemogenetically inhibiting vDG excitatory neurons within the first 24 h after ARS completely abolished the anxiolytic effects of poststress social isolation, while stimulating vDG excitatory neurons remarkably reduced anxiety-like behaviors in the poststress social contact group. Together, these data suggest that the activity of vDG excitatory neurons is essential and sufficient to govern the anxiolytic effect of poststress social isolation. To the best of our knowledge, this is the first report to uncover a beneficial role of temporal social isolation in acute stress-induced anxiety. In addition to the critical 24-h time window, activation of vDG is crucial for ameliorating anxiety through poststress social isolation.

Alcohol consumption modulates prelimbic cortex response to cocaine following sequential cocaine and alcohol polysubstance use in the rat.

Polysubstance use (PSU), involves the consumption of more than one drug within a period of time and is prevalent among cocaine users. Ceftriaxone, a beta-lactam antibiotic, reliably attenuates reinstatement of cocaine seeking in pre-clinical models by restoring glutamate homeostasis following cocaine self-administration but fails to do so when rats consume both cocaine and alcohol (cocaine + alcohol PSU). We previously found that cocaine + alcohol PSU rats reinstate cocaine seeking similarly to cocaine-only rats, but demonstrate differences in reinstatement-induced c-Fos expression throughout the reward system, including a lack of change upon ceftriaxone treatment. Here, we used this model to determine if previous findings were caused by tolerance or sensitization to the pharmacological effects of cocaine. Male rats underwent intravenous cocaine self-administration immediately followed by 6h of home cage access to water or unsweetened alcohol for 12days. Rats subsequently underwent 10 daily instrumental extinction sessions, during which time they were treated with either vehicle or ceftriaxone. Rats then received a non-contingent cocaine injection and were perfused for later immunohistochemical analysis of c-Fos expression in the reward neurocircuitry. c-Fos expression in the prelimbic cortex correlated with total alcohol intake in PSU rats. There were no effects of either ceftriaxone or PSU on c-Fos expression in the infralimbic cortex, nucleus accumbens core and shell, basolateral amygdala, or ventral tegmental area. These results support the idea that PSU and ceftriaxone alter the neurobiology underlying drug-seeking behavior in the absence of pharmacological tolerance or sensitization to cocaine.

Corticosterone injection into the infralimbic prefrontal cortex enhances fear memory extinction: Involvement of GABA receptors and the extracellular signal-regulated kinase

This study investigated the interactive effect of glucocorticoid and Gamma-aminobutyric acid (GABA) receptors in the Infralimbic (IL) cortex on fear extinction in rats' auditory fear conditioning task (AFC).Animals received 3 conditioning trial tones (conditioned stimulus, 30 s, 4 kHz, 80 dB) co-terminated with a footshock (unconditioned stimulus, 0.8 mA, 1 s). Extinction testing was conducted over 3 days (Ext 1–3) after conditioning. Intra-IL injection of corticosterone (CORT, 20 ng/0.3 µl/side) was performed 15 min before the first extinction trial (Ext 1) which attenuated auditory fear expression in subsequent extinction trials (Ext 1–3), demonstrating fear memory extinction enhancement. Co-injection of the GABAA agonist muscimol (250 ng/0.3 µl/side) or the GABAB agonist baclofen (250 ng/0.3 µl/side) 15 min before corticosterone, did not significantly affect the facilitative effects of corticosterone on fear extinction. However, co-injection of the GABAA antagonist bicuculline (BIC, 100 ng/0.3 µl/side) or the GABAB antagonist CGP35348 (CGP, 100 ng/0.3 µl/side) 15 min before corticosterone, blocked the facilitative effects of corticosterone on fear extinction. Moreover, extracellular signal-regulated kinase (ERK) and cAMP response element-binding (CREB) in the IL were examined by Western blotting analysis after the first extinction trial (Ext 1) in some groups. Intra-IL injection of corticosterone increased the ERK activity but not CREB. Co-injection of the bicuculline or CGP35348 blocked the enhancing effect of corticosterone on ERK expression in the IL.Glucocorticoid receptors (GRs) activation in the IL cortex by corticosterone increased ERK activity and facilitated fear extinction. GABAA or GABAB antagonists decreased ERK activity and inhibited corticosterone's effect. GRs and GABA receptors in the IL cortex jointly modulate the fear extinction processes via the ERK pathway. This pre-clinical animal study may highlight GRs and GABA interactions in the IL cortex modulating fear memory processes in fear-related disorders such as post-traumatic stress disorder (PTSD).

Differential Modulation of Dorsal Raphe Serotonergic Activity in Rat Brain by the Infralimbic and Prelimbic Cortices

The reciprocal connectivity between the medial prefrontal cortex (mPFC) and the dorsal raphe nucleus (DR) is involved in mood control and resilience to stress. The infralimbic subdivision (IL) of the mPFC is the rodent equivalent of the ventral anterior cingulate cortex, which is intimately related to the pathophysiology/treatment of major depressive disorder (MDD). Boosting excitatory neurotransmission in the IL-but not in the prelimbic cortex, PrL-evokes depressive-like or antidepressant-like behaviors in rodents, which are associated with changes in serotonergic (5-HT) neurotransmission. We therefore examined the control of 5-HT activity by both of the mPFC subdivisions in anesthetized rats. The electrical stimulation of IL and PrL at 0.9 Hz comparably inhibited 5-HT neurons (53% vs. 48%, respectively). However, stimulation at higher frequencies (10-20 Hz) revealed a greater proportion of 5-HT neurons sensitive to IL than to PrL stimulation (86% vs. 59%, at 20 Hz, respectively), together with a differential involvement of GABAA (but not 5-HT1A) receptors. Likewise, electrical and optogenetic stimulation of IL and PrL enhanced 5-HT release in DR in a frequency-dependent manner, with greater elevations after IL stimulation at 20 Hz. Hence, IL and PrL differentially control serotonergic activity, with an apparent superior role of IL, an observation that may help to clarify the brain circuits involved in MDD.

Contextual fear conditioning with a time interval induces CREB phosphorylation in the dorsal hippocampus and amygdala nuclei that depend on prelimbic cortex activity.

In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity-dependent changes or indirectly, by modulation of activity-dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre-training PL inactivation by muscimol in CREB (cAMP response element-binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3h after the training in the contextual fear conditioning (CFC) or CFC with 5-s interval (CFC-5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC-5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC-5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC-5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning-induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation.

Compensatory Contextual Fear Memory Pathways Develop in the Infralimbic Cortex within 3 Days after the First Test in the Absence of the Dorsal Hippocampus.

The dorsal hippocampus (DH) is primarily involved in the formation of contextual fear-conditioned (CxFC) memory. However, CxFC memory can be formed even in the absence of the DH. In addition to the DH, the infralimbic cortex (IL), a sub-region of the medial prefrontal cortex (mPFC), also plays an important role in the consolidation of CxFC memory. However, role of IL in the development of compensatory CxFC memory is not known. Here, we have examined (a) the development of the compensatory circuitry of CxFC memory within 3 days after the first test in the absence of the DH and (b) the role of IL in the induction of compensatory CxFC memory in the absence of the DH. The DH-lesioned rats re-trained for CxFC 1 day after the first testing exhibited significantly less freezing compared to the control group. However, the DH-lesioned rats, re-trained for CxFC 3 days after the first testing, showed a robust freezing response. It suggests that the fully functional compensatory circuitry of contextual fear memory develops after multiple training separated by 3 days. Furthermore, we observed that reversible inactivation of the IL of the DH-lesioned rats during the first training waned the formation of compensatory CxFC. It suggests that (a) the IL receives contextual fear memory information during the first trial in the absence of the DH and (b) perturbation in fear memory information encoding in the IL during the first trial impairs the development of the compensatory network in the absence of the DH.

Animal models of human insomnia.

Insomnia disorder (chronic sleep continuity disturbance) is a debilitating condition affecting 5%-10% of the adult population worldwide. To date, researchers have attempted to model insomnia in animals through breeding strategies that create pathologically short-sleeping individuals or with drugs and environmental contexts that directly impose sleeplessness. While these approaches have been invaluable for identifying insomnia susceptibility genes and mapping the neural networks that underpin sleep-wake regulation, they fail to capture concurrently several of the core clinical diagnostic features of insomnia disorder in humans, where sleep continuity disturbance is self-perpetuating, occurs despite adequate sleep opportunity, and is often not accompanied by significant changes in sleep duration or architecture. In the present review, we discuss these issues and then outline ways animal models can be used to develop approaches that are more ecologically valid in their recapitulation of chronic insomnia's natural aetiology and pathophysiology. Conditioning of self-generated sleep loss with these methods promises to create a better understanding of the neuroadaptations that maintain insomnia, including potentially within the infralimbic cortex, a substrate at the crossroads of threat habituation and sleep.

A new circuit underlying the renewal of appetitive Pavlovian responses: Commentary on Brown and Chaudhri (2022).

A new circuit underlying the renewal of appetitive Pavlovian responses: Commentary on Brown and Chaudhri (2022).

Competing contextual processes rely on the infralimbic and prelimbic medial prefrontal cortices in the rat.

Ambiguous relationships between events may be established using interference procedures such as latent inhibition, extinction or counterconditioning. Under these conditions, the retrieval of individual associations between a stimulus and outcome is affected by contextual cues. To examine the roles of the dorsal (prelimbic) and ventral (infralimbic) medial prefrontal cortex in the contextual modulation of such associations, we investigated the context specificity of latent inhibition. Male Lister hooded rats were pre-exposed to two separate stimuli, one in each of two distinct contexts. Both stimuli were then paired with the delivery of mild foot-shock in the same one of these contexts. Finally, the strength of the resultant conditioned emotional response (CER) to each stimulus was assessed in each context. For the sham-operated control rats, the CER was attenuated for each stimulus when it was tested in the context in which it had been pre-exposed. Rats who had received lesions to the infralimbic cortex showed this effect only in the conditioning context, whereas rats with lesions to the prelimbic cortex showed the effect only in the context in which conditioning had not taken place. These findings indicate that infralimbic and prelimbic cortices play distinct, and competing, roles in the contextual modulation of initial and later learning.

Touchscreen-Based Cognitive Training Alters Functional Connectivity Patterns in Aged But Not Young Male Rats.

Age-related cognitive decline is related to cellular and systems-level disruptions across multiple brain regions. Because age-related cellular changes within different structures do not show the same patterns of dysfunction, interventions aimed at optimizing function of large-scale brain networks may show greater efficacy at improving cognitive outcomes in older adults than traditional pharmacotherapies. The current study aimed to leverage a preclinical rat model of aging to determine whether cognitive training in young and aged male rats with a computerized paired-associates learning (PAL) task resulted in changes in global resting-state functional connectivity. Moreover, seed-based functional connectivity was used to examine resting state connectivity of cortical areas involved in object-location associative memory and vulnerable in old age, namely the medial temporal lobe (MTL; hippocampal cortex and perirhinal cortex), retrosplenial cortex (RSC), and frontal cortical areas (prelimbic and infralimbic cortices). There was an age-related increase in global functional connectivity between baseline and post-training resting state scans in aged, cognitively trained rats. This change in connectivity following cognitive training was not observed in young animals, or rats that traversed a track for a reward between scan sessions. Relatedly, an increase in connectivity between perirhinal and prelimbic cortices, as well as reduced reciprocal connectivity within the RSC, was found in aged rats that underwent cognitive training, but not the other groups. Subnetwork activation was associated with task performance across age groups. Greater global functional connectivity and connectivity between task-relevant brain regions may elucidate compensatory mechanisms that can be engaged by cognitive training.

Characterisation of the neural basis underlying appetitive extinction & renewal in Cacna1c rats

Recent studies have revealed impairments in Cacna1c ± heterozygous animals (a gene that encodes the Cav 1.2 L-type voltage-gated calcium channels and is implicated in risk for multiple neuropsychiatric disorders) in aversive forms of learning, such as latent inhibition, reversal learning or context discrimination. However, the role of Cav 1.2 L-type voltage-gated calcium channels in extinction of appetitive associations remains under-investigated. Here, we used an appetitive Pavlovian conditioning task and evaluated extinction learning (EL) with a change of context from that of training and test (ABA) and without such a change (AAA) in Cacna1c ± male rats versus their wild-type (WT) littermates. In addition, we used fluorescence in situ hybridization of somatic immediate early genes (IEGs) Arc and Homer1a expression to scrutinize associated changes in the medial prefrontal cortex and the amygdala. Cacna1c ± animals successfully adapt their responses by engaging in appetitive EL and renewal. However, the regional IEG expression profile changed. For the EL occurring in the same context, Cacna1c ± animals presented higher IEG expression in the infralimbic cortex and the central amygdala than controls. The prelimbic region presented a larger neural ensemble in Cacna1c ± than WT animals, co-labelled for the time window of EL in the original context and prolonged exposure to the unrewarded context. With a context change, the Cacna1c ± infralimbic region displayed higher IEG expression during renewal than controls. Taken together, our findings provide novel evidence of distinct brain activation patterns occurring in Cacna1c ± rats after appetitive extinction and renewal despite preserved behavioral responses.This article is part of the Special Issue on "L-type calcium channel mechanisms in neuropsychiatric disorders".

Correction to: Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex

Correction to: Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex

β-adrenoceptors of the infra-limbic cortex mediate corticosterone-induced enhancement of acquisition and consolidation of fear memory extinction in rats

The extinction of auditory fear conditioning (AFC) refers to reducing the fear responses induced following repeated presentation of a conditioned stimulus (tone) in the absence of an unconditioned stimulus (electric foot shock). Glucocorticoid receptors (GRs) play an important role in extinction, but the underlying neurobiological mechanisms are unclear. This study aimed to investigate the interaction between glucocorticoids and β-adrenoceptors of the infra-limbic cortex (IL) in regulating the acquisition and consolidation of fear memory extinction in rats. Male rats were trained to AFC and received three trial tones (30 s, 4 kHz, 80 dB) co-terminated with a footshock (0.8 mA, 1 s; unconditioned stimulus). Extinction trials were conducted over 3 days after training (Ext 1–3). In experiment 1, rats received clenbuterol (0.25 mg/kg/2 ml, IP) as a β2-adrenoceptor agonist or propranolol (2.5 mg/kg/2 ml, IP) as a β-adrenoceptors antagonist before Ext 1 and immediately after Ext 1 and Ext 2 followed by systemic injection of corticosterone (3 mg/kg/2 ml, IP). In Experiment 2, separate groups of rats received a bilateral intra-IL injection of clenbuterol (50 ng/0.5 µl/side) or propranolol (500 ng/0.5 µl/side) followed by a systemic injection of corticosterone (3 mg/kg/2 ml) before Ext 1 and immediately after Ext 1 and Ext 2. Results indicated that systemic and intra-IL injections of clenbuterol and propranolol inhibited and increased the facilitative effects of corticosterone on fear memory extinction, respectively. These findings show that activating β-adrenergic receptors in the IL mediates glucocorticoid effects on the acquisition and consolidation of auditory-conditioned fear memory extinction.