Neurobiological correlates of high (HAB) versus low anxiety-related behavior (LAB): differential Fos expression in HAB and LAB rats.

BACKGROUND: Two Wistar rat lines selectively bred for either high (HAB) or low (LAB) anxiety-related behavior were used to identify neurobiological correlates of trait anxiety. METHODS: We used Fos expression for mapping of neuronal activation patterns in response to mild anxiety-provoking challenges. RESULTS: In both lines, exposure to an open field (OF) or the open arm (OA) of an elevated plus-maze induced Fos expression in several brain areas of the anxiety/fear circuitry. Rats of the HAB type, which showed signs of a hyperanxious phenotype and a hyperreactive hypothalamic-pituitary-adrenal axis compared with LAB rats, exhibited a higher number of Fos-positive cells in the paraventricular nucleus of the hypothalamus, the lateral and anterior hypothalamic area, and the medial preoptic area in response to both OA and OF. Less Fos expression was induced in the cingulate cortex in HAB than in LAB rats. Differential Fos expression in response to either OA or OF was observed in few brain regions, including the thalamus and hippocampus. CONCLUSIONS: The present data indicate that the divergent anxiety-related behavioral response of HAB versus LAB rats to OF and OA exposures is associated with differential neuronal activation in restricted parts of the anxiety/fear circuitry. Distinct hypothalamic regions displayed hyperexcitability, and the cingulate cortex showed hypoexcitability, which suggests that they are main candidate mediators of dysfunctional brain activation in pathologic anxiety.     

β‐Amyloid pathology alters neural network activation during retrieval of contextual fear memories in a mouse model of Alzheimer's disease

Although episodic memory deficits are the most conspicuous cognitive change in patients with Alzheimer's disease (AD), patients also display alterations in emotional expression, including anxiety and impaired conditioned fear behaviours. The neural circuitry underlying emotional learning is known to involve the amygdala and hippocampus, although the precise impact of amyloid pathology on the interaction between these brain regions remains unclear. Recent evidence suggests that Tg2576 mice, which express a human amyloid precursor protein (APP) mutation associated with early‐onset AD, demonstrate normal acquisition of conditioned freezing to auditory and contextual stimuli paired with footshock. However, examination of the expression of c‐Fos revealed altered neural network activity in transgenic mice. In the present study we examined the effects of the APP mutation on the expression of c‐Fos following the retrieval of emotional memories. To this end, stimulus‐induced cellular activity was measured by analysing expression of the immediate‐early gene c‐Fos after the retrieval of auditory or contextual fear memories. To characterize regional interdependencies of c‐Fos expression, structural equation modelling was used to compare patterns of neural network activity. Consistent with previous findings, Tg2576 mice displayed reduced freezing elicited by the auditory stimulus but not by the conditioning context. Interestingly, the analysis of c‐Fos expression revealed that the APPswe mutation disrupted dentate gyrus and amygdala function, as well as altering the influence of these regions on the neural network dynamics activated during context memory retrieval. These results provide novel insight into the influence of excess amyloid production on neural network activity during memory retrieval.     

Two types of social buffering differentially mitigate conditioned fear responses

In a phenomenon known as 'social buffering' in various species, signals from a conspecific animal can mitigate stress responses. This buffering can be achieved either by 'pair-housing' after a stressful event or by 'pair-exposure' to an acute stressor with a conspecific animal. In this study, we compared the impacts of these two types of social buffering on auditory conditioned fear responses in male rats. When subjects were exposed to an auditory conditioned stimulus (CS) that had been paired with foot shocks on the previous day, they clearly exhibited behavioral (freezing), autonomic (aggravated stress-induced hyperthermia) and neural (Fos expression) responses. Pair-housing for 24 h with an unfamiliar rat following fear conditioning resulted in a suppressed autonomic, but not behavioral, response, with Fos expression in the lateral nucleus of the amygdala and ventrolateral periaqueductal gray. On the other hand, pair-exposure to the CS with an unfamiliar rat eliminated the behavioral, but not the autonomic, response, with Fos expression in the basal nucleus of the amygdala and infralimbic region of the prefrontal cortex. Furthermore, subjects that had been pair-housed and then pair-exposed showed no behavioral, autonomic or neural responses, suggesting that the combination of the two procedures can completely block the fear conditioning sequence. These results demonstrate that two types of social buffering differentially relieve conditioned fear responses, by influencing different neural pathways in the amygdala.     

Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response

The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two‐stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear‐conditioned responses in the amygdala and slow conditioning of motor‐conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum‐dependent motor‐conditioned responses was associated with a decrease in amygdala‐dependent fear‐conditioned responses, and was interpreted as extinction of amygdala‐related fear‐conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal‐conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy.     

Behavioral and paired-pulse facilitation analyses of long-lasting depression at excitatory synapses in the medial prefrontal cortex in mice

Accumulative evidence indicates that acute (before extinction) and long-lasting (during extinction) depression can occur at excitatory synapses in mouse medial prefrontal cortex (mPFC) during re-exposure to a tone (conditioned stimulus: CS), previously paired with footshock (unconditioned stimulus: US). As recently shown, the long-term depression (LTD)-like plasticity in the mPFC does not interfere with extinction of CS-evoked freezing but predicts spontaneous recovery of this fear response. Here, the objectives were to investigate: (i). whether a resistance to extinction without any prefrontal acute synaptic plasticity could produce LTD-like changes, and (ii). by the use of paired-pulse facilitation (PPF) analyses, whether pre- or post-synaptic mechanisms were involved in this LTD phenomenon. Preliminary analyses indicated that levels of acute depression did not correlate with the degree of fear acquisition (effects of number of CS-US pairings). As a consequence, mice conditioned with 2CS+ or 2CS+/2CS- (partial reinforcement of the CS known to induce resistance to extinction) exhibited CS-associated freezing without any acute synaptic depression in the mPFC. However, during further CS-alone presentations, the 2CS+/2CS- group developed LTD-like changes that accompanied their resistance to extinguish freezing to the CS. In contrast, the 2CS+ group normally extinguished their conditioned freezing with synaptic transmission remaining at baseline levels. PPF analyses revealed that facilitation was unchanged following prefrontal LTD. These data, combined with our previous findings, (i). support a critical involvement of prefrontal LTD-like changes in spontaneous recovery of fear responses, and (ii). suggest a post-synaptic site for these changes.     

NMDA receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian fear conditioning in rats

Glutamate receptors in the basolateral complex of the amygdala (BLA) are essential for the acquisition, expression and extinction of Pavlovian fear conditioning in rats. Recent work has revealed that glutamate receptors in the central nucleus of the amygdala (CEA) are also involved in the acquisition of conditional fear, but it is not known whether they play a role in fear extinction. Here we examine this issue by infusing glutamate receptor antagonists into the BLA or CEA prior to the extinction of fear to an auditory conditioned stimulus (CS) in rats. Infusion of the α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptor antagonist, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo[f]quinoxaline‐2,3‐dione (NBQX), into either the CEA or BLA impaired the expression of conditioned freezing to the auditory CS, but did not impair the formation of a long‐term extinction memory to that CS. In contrast, infusion of the N‐methyl‐d ‐aspartate (NMDA) receptor antagonist, d,l ‐2‐amino‐5‐phosphonopentanoic acid (APV), into the amygdala, spared the expression of fear to the CS during extinction training, but impaired the acquisition of a long‐term extinction memory. Importantly, only APV infusions into the BLA impaired extinction memory. These results reveal that AMPA and NMDA receptors within the amygdala make dissociable contributions to the expression and extinction of conditioned fear, respectively. Moreover, they indicate that NMDA receptor‐dependent processes involved in extinction learning are localized to the BLA. Together with previous work, these results reveal that NMDA receptors in the CEA have a selective role acquisition of fear memory.     

Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons

Stress‐sensitive psychopathologies such as post‐traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex‐to‐BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non‐conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress‐related disorders.     

A role for anterior thalamic nuclei in affective cognition: Interaction with environmental conditions

Damage to anterior thalamic nuclei (ATN) is a well‐known cause of diencephalic pathology that produces a range of cognitive deficits reminiscent of a hippocampal syndrome. Anatomical connections of the ATN also extend to cerebral areas that support affective cognition. Enriched environments promote recovery of declarative/relational memory after ATN lesions and are known to downregulate emotional behaviors. Hence, the performance of standard‐housed and enriched ATN rats in a range of behavioral tasks engaging affective cognition was compared. ATN rats exhibited reduced anxiety responses in the elevated plus maze, increased activity and reduced corticosterone responses when exploring an open field, and delayed acquisition of a conditioned contextual fear response. ATN rats also exhibited reduced c‐Fos and phosphorylated cAMP response element‐binding protein (pCREB) immunoreactivity in the hippocampal formation and the amygdala after completion of the contextual fear test. Marked c‐Fos hypoactivity and reduced pCREB levels were also evident in the granular retrosplenial cortex and, to a lesser extent, in the anterior cingulate cortex. Unlike standard‐housed ATN rats, enriched ATN rats expressed virtually no fear of the conditioned context. These results show that the ATN regulate affective cognition and that damage to this region may produce markedly different behavioral effects as a function of environmental housing conditions. © 2013 Wiley Periodicals, Inc.     

The T‐type calcium channel blocker Z944 reduces conditioned fear in Genetic Absence Epilepsy Rats from Strasbourg and the non‐epileptic control strain

Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are a rodent model of childhood absence epilepsy (CAE) that display a gain‐of‐function mutation in the gene encoding the Cav3.2 T‐type calcium channel. GAERS demonstrate heightened learning and delayed extinction of fear conditioning. Our objective in the present study was to examine the effects of the pan‐T‐type calcium channel blocker Z944 on the acquisition, consolidation and extinction of conditioned fear in GAERS and the non‐epileptic control (NEC) strain. Z944 (10 mg/kg; ip) was administered 15 min prior to either acquisition, extinction day 1 (24 hr later), acquisition and extinction day 1, or during the consolidation (post‐acquisition) of tone‐cued fear conditioning. Extinction was examined 24 and 48 hr after conditioning. In drug naïve GAERS, increased freezing during the acquisition and extinction phases of fear conditioning was found. Short‐term effects of Z944 on performance were observed as Z944 increased freezing during testing on the day it was administered. Z944 administered prior to the acquisition phase had a long‐term effect on extinction. Specifically, both GAERS and NECs showed a decrease in freezing during extinction relative to drug naïve GAERS and NEC rats respectively. Regardless of strain or treatment, female rats showed reduced extinction of fear relative to male rats. These results demonstrate that T‐type calcium channels contribute to the neural systems that mediate the learning and memory of conditioned fear. Overall, these findings suggest that T‐type calcium channel blockers show promise in the treatment of learning impairments observed in disorders such as CAE.     

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

Background

Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event.

Effects of D-cycloserine and midazolam on the expression of the GABA-A alpha-2 receptor subunits in brain structures of fear conditioned rats

The role of the GABA-A alpha-2 receptor subunit in the basolateral amygdala (BLA), dentate gyrus of the hippocampus (DG) and prefrontal cortex (M2 area) during a fear session (performed one week after the conditioned fear test), was studied. We employed a model of high (HR) and low anxiety (LR) rats divided according to their conditioned freezing response. Pretreatment of rats with d-cycloserine immediately before the fear session attenuated fear response in HR and LR rats and increased the density of alpha-2 subunits in the BLA, M2 area and DG of HR animals. The less potent behavioural influence of midazolam (in HR group only) was linked to the increased expression of alpha-2 subunit in M2 area and DG. These results support a role of the GABA-A receptor alpha-2 subunit in processing of emotional cortico-hippocampal input to the BLA.     

Social Synchronization of Conditioned Fear in Mice Requires Ventral Hippocampus Input to the Amygdala

BackgroundSocial organisms synchronize behaviors as an evolutionary-conserved means of thriving. Synchronization under threat, in particular, benefits survival and occurs across species, including humans, but the underlying mechanisms remain unknown because of the scarcity of relevant animal models. Here, we developed a rodent paradigm in which mice synchronized a classically conditioned fear response and identified an underlying neuronal circuit.MethodsMale and female mice were trained individually using auditory fear conditioning and then tested 24 hours later as dyads while allowing unrestricted social interaction during exposure to the conditioned stimulus under visible or infrared illumination to eliminate visual cues. The synchronization of the immobility or freezing bouts was quantified by calculating the effect size Cohen’s d for the difference between the actual freezing time overlap and the overlap by chance. The inactivation of the dorsomedial prefrontal cortex, dorsal hippocampus, or ventral hippocampus was achieved by local infusions of muscimol. The chemogenetic disconnection of the hippocampus-amygdala pathway was performed by expressing hM4D(Gi) in the ventral hippocampal neurons and infusing clozapine N-oxide in the amygdala.ResultsMice synchronized cued but not contextual fear. It was higher in males than in females and attenuated in the absence of visible light. Inactivation of the ventral but not dorsal hippocampus or dorsomedial prefrontal cortex abolished fear synchronization. Finally, the disconnection of the hippocampus-amygdala pathway diminished fear synchronization.ConclusionsMice synchronize expression of conditioned fear relying on the ventral hippocampus-amygdala pathway, suggesting that the hippocampus transmits social information to the amygdala to synchronize threat response.     

An antisense oligonucleotide reverses the footshock-induced expression of fos in the rat medial prefrontal cortex and the subsequent expression of conditioned fear-induced immobility.

The immediate-early genes, including c-fos, have been proposed to be involved in learning and memory. In this report, we examine stress-induced Fos-like immunoreactivity (Fos-li) in subregions of the prefrontal cortex during a conditioned fear paradigm. During the acquisition phase, the rats were conditioned to fear a formerly neutral tone by pairing the tone with a mild footshock. The rats were then tested for fearful behavior by reexposure to the tone without additional footshock. During acquisition, Fos-li was increased in the medial prefrontal cortex (infralimbic and prelimbic) but not the anterior cingulate and M1 motor cortex. However, during the extinction phase, no significant increase in Fos-li was observed in any region. These findings indicate that acquisition, but not extinction, of conditioned fear is associated with an increase in Fos-li in subregions of the medial prefrontal cortex. In other animals, an antisense oligonucleotide directed against the c-fos mRNA was injected into the infralimbic/prelimbic cortex 12 or 72 hr before the acquisition session. Antisense treatment given 12, but not 72, hr earlier suppressed Fos production without altering behavior during the acquisition session. Three days after the acquisition session, rats were tested for fearful behavior as before. The antisense oligonucleotide blockade of Fos production during acquisition was associated with a significantly less fearful response during the extinction session. These results support a role for Fos in the medial prefrontal cortex during the acquisition of aversive learning.     

Impaired extinction of fear and maintained amygdala-hippocampal theta synchrony in a mouse model of temporal lobe epilepsy

Purpose: The relationship between epilepsy and fear has received much attention. However, seizure‐modulated fear and physiologic or structural correlates have not been examined systematically, and the underlying basics of network levels remain unclear to date. Therefore, this project was set up to characterize the neurophysiologic basis of seizure‐related fear and the contribution of the amygdala‐hippocampus system. Methods: The experimental strategy was composed of the following steps: (1) use of the mouse pilocarpine model of temporal lobe epilepsy (TLE); (2) behavioral analyses of anxiety states in the elevated plus maze test, light–dark avoidance test, and Pavlovian fear conditioning; and (3) probing neurophysiologic activity patterns in amygdala‐hippocampal circuits in freely behaving mice. Results: Our results displayed no significant differences in basic anxiety levels comparing mice that developed spontaneous recurrent seizures (SRS) and controls. Furthermore, conditioned fear memory retrieval was not influenced in SRS mice. However, during fear memory extinction, SRS mice showed an extended freezing behavior and a maintained amygdala‐hippocampal theta frequency synchronization compared to controls. Discussion: These results indicate specific alterations in conditioned fear behavior and related neurophysiologic activities in the amygdala‐hippocampal network contributing to impaired fear memory extinction in mice with TLE. Clinically, the nonextinguished fear memories may well contribute to the experience of fear in patients with TLE.     

The role of the dorsomedial part of the prefrontal cortex serotonergic innervation in rat responses to the aversively conditioned context: behavioral, biochemical and immunocytochemical studies

In this study we have explored differences in animal reactivity to conditioned aversive stimuli using the conditioned fear test (a contextual fear-freezing response), in rats subjected to the selective lesion of the prefrontal cortex serotonergic innervation, and differing in their response to the acute painful stimulation, a footshock (HS--high sensitivity rats, and LS--low sensitivity rats, selected arbitrarily according to their behavior in the 'flinch-jump' pre-test). Local administration of serotonergic neurotoxin (5,7-dihydroxytryptamine) to the dorsomedial part of the prefrontal cortex caused a very strong, structure and neurotransmitter selective depletion of serotonin concentration. In HS rats, the serotonergic lesion significantly disinhibited rat behavior controlled by fear, enhanced c-Fos expression in the dorsomedial prefrontal area, and increased the concentration of GABA in the basolateral amygdala, measured in vivo after the testing session of the conditioned fear test. The LS animals revealed an opposite pattern of behavioral and biochemical changes after serotonergic lesion: an increase in the duration of a freezing response, and expression of c-Fos in the basolateral and central nuclei of amygdala, and a lower GABA concentration in the basolateral amygdala. In control conditions, c-Fos expression did not differ in LS and HS, na?ve, not conditioned and not exposed to the test cage animals. The present study adds more arguments for the controlling role of serotonergic innervation of the dorsomedial part of the prefrontal cortex in processing emotional input by other brain centers. Moreover, it provides experimental data, which may help to better explain the anatomical and biochemical basis of differences in individual reactivity to stressful stimulation, and, possibly, to anxiolytic drugs with serotonergic or GABAergic profiles of action.     

Acoustic startle and fear-potentiated startle in rats selectively bred for fast and slow kindling rates: relation to monoamine activity

The acoustic startle response, prepulse inhibition, fear-potentiated startle and monoamine activity induced by either, a novel stimulus or a cue previously paired with foot-shock (fear-conditioning), were assessed in rats selectively bred for differences in amygdala excitability (Fast vs. Slow kindling epileptogenesis). Comorbid differences of anxiety, which were dependent both on the rats' behavioural style and the kind of stressor, also characterized these strains. In the present investigation, Slow rats exhibited a greater startle reflex to noise relative to Fast rats, suggesting differences in generalized anxiety, but similar rates of startle habituation and prepulse inhibition. The fear-potentiated startle, however, was greater in Fast rats. When movement of the rat was restricted in a new environment, presentation of a novel stimulus (light) increased norepinephrine, dopamine and/or serotonin activity in brain regions typically associated with stressors (e.g. locus coeruleus, paraventricular hypothalamic nucleus). Generally, these effects were more pronounced in Fast rats, and norepinephrine utilization in the central amygdala was particularly highlighted in response to a conditioned fear stimulus. Thus, while generalized anxiety appeared greater in Slow rats, behavioural and central neurochemical reactivity in response to novel stimuli and to fear-eliciting stimuli, was greater in Fast rats. Similarly, basal dopamine activity in the prefrontal cortex was greater in Fast rats, but dopamine utilization elicited by a novel stimulus was more pronounced in Slow rats. This suggested that relative to Slow rats, dopamine neurons in prefrontal cortex of Fast rats do not react normally to environmental stimuli, and this phenomenon could lead to disturbances of attention or impulsivity.     

Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex.

What brain regions are involved in regulating behavior when the emotional consequence of a stimulus changes from harmful to harmless? One way to address this question is to study the neural mechanisms underlying extinction of Pavlovian fear conditioning, an important form of emotional regulation that has direct relevance to the treatment of human fear and anxiety disorders. In fear extinction, the capacity of a conditioned stimulus to elicit fear is gradually reduced by repeatedly presenting it in the absence of any aversive consequence. In recent years there has been a dramatic increase in research on the brain mechanisms of fear extinction. One region that has received considerable attention as a component of the brain's extinction circuitry is the medial prefrontal cortex (mPFC). In the present article, we review the historical foundations of the modern notion that the mPFC plays a critical role in emotional regulation, a literature that was largely responsible for studies that explored the role of the mPFC in fear extinction. We also consider the role of the mPFC in a broader neural circuit for extinction that includes the amygdala and hippocampus.     

D-cycloserine facilitates extinction of learned fear: effects on reacquisition and generalized extinction.

BACKGROUND: d-cycloserine (DCS) facilitates extinction of learned fear. The aim of this study was to examine whether DCS 1) affects reacquisition of fear (Experiment 1) and 2) produces generalized extinction of fear (Experiment 2). METHODS: Following fear conditioning, where a light or a tone conditioned stimulus (CS) was paired with a white-noise burst unconditioned stimulus (US), rats received nonreinforced exposure to one CS (i.e., extinction training). Fear was assessed by measuring CS-elicited freezing, a species-specific defense response. RESULTS: Rats given DCS exhibited facilitated extinction of fear but were able to reacquire fear of that CS in a similar manner as saline-treated control animals (Experiment 1). Furthermore, DCS-treated rats exhibited generalized extinction (i.e., they were less fearful of a non-extinguished CS) in comparison to controls (Experiment 2). CONCLUSIONS: DCS facilitates extinction of learned fear to the extinguished CS, but also appears to reduce fear of a nonextinguished CS. These findings suggest that this drug may have substantial clinical value in the treatment of anxiety disorders.     

Pharmacological enhancement of calcium-activated potassium channel function reduces the effects of repeated stress on fear memory

Repeated stress impacts emotion, and can induce mood and anxiety disorders. These disorders are characterized by imbalance of emotional responses. The amygdala is fundamental in expression of emotion, and is hyperactive in many patients with mood or anxiety disorders. Stress also leads to hyperactivity of the amygdala in humans. In rodent studies, repeated stress causes hyperactivity of the amygdala, and increases fear conditioning behavior that is mediated by the basolateral amygdala (BLA). Calcium-activated potassium (K(Ca)) channels regulate BLA neuronal activity, and evidence suggests reduced small conductance K(Ca) (SK) channel function in male rats exposed to repeated stress. Pharmacological enhancement of SK channels reverses the BLA neuronal hyperexcitability caused by repeated stress. However, it is not known if pharmacological targeting of SK channels can repair the effects of repeated stress on amygdala-dependent behaviors. The purpose of this study was to test whether enhancement of SK channel function reverses the effects of repeated restraint on BLA-dependent auditory fear conditioning. We found that repeated restraint stress increased the expression of cued conditioned fear in male rats. However, 1-Ethyl-2-benzimidazolinone (1-EBIO, 1 or 10 mg/kg) or CyPPA (5 mg/kg) administered 30 min prior to testing of fear expression brought conditioned freezing to control levels, with little impact on fear expression in control handled rats. These results demonstrate that enhancement of SK channel function can reduce the abnormalities of BLA-dependent fear memory caused by repeated stress. Furthermore, this indicates that pharmacological targeting of SK channels may provide a novel target for alleviation of psychiatric symptoms associated with amygdala hyperactivity.     

Vasopressin released within the central amygdala promotes maternal aggression

Vasopressin regulates important aspects of social behaviour. Although vasopressin is more prominent in the expression of male social behaviours, we recently demonstrated its role in the fine‐tuned maintenance of maternal care in lactating rats. Here, we investigate the involvement of brain vasopressin in the regulation of maternal aggression in lactating Wistar rats selectively bred for either high (HAB) or low (LAB) anxiety‐related behaviour. The genetically determined elevation in vasopressin mRNA expression was confirmed within the hypothalamic paraventricular nucleus of virgin and lactating HAB rats and was additionally found in limbic brain areas. Lactating HAB dams are more maternally aggressive as part of their generally higher level of maternal care compared with LAB rats. Using intracerebral microdialysis, we describe increased vasopressin release within the central amygdala, but not the paraventricular nucleus, during maternal aggression only in HAB dams. Moreover, the release of vasopressin within the central amygdala was positively correlated with the display of offensive behaviour. Blockade of local vasopressin actions by bilateral administration of a selective vasopressin V1a receptor antagonist into the central amygdala reduced maternal aggression in HAB dams, whereas synthetic vasopressin increased the low level of aggression in LAB rats. Vasopressin receptor binding within the central amygdala or the paraventricular nucleus was similar in HAB and LAB females. In conclusion, vasopressin is an important neuropeptide regulating maternal aggressive behaviour, thus further extending its involvement in female social behaviour. Differences in intracerebral vasopressin release within the central amygdala rather than local vasopressin receptor binding contribute to the level of maternal aggression.