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Abstract: Previous data suggest that overtraining can overcome fear conditioning deficits in rats with lesions of the basolateral complex of the amygdala (BLA). We have previously shown that the central nucleus of the amygdala (CEA) is essential for the acquisition and expression of conditional fear to both contextual and auditory conditioned stimuli (CSs) after overtraining. This provides strong evidence that the CEA can compensate for the loss of the BLA. Another brain area that may compensate for the loss of the BLA is the bed nucleus of the stria terminalis (BNST). We explored this possibility by examining the consequences of lesions or reversible inactivation of the BNST on the expression of overtrained fear in rats with BLA lesions. We demonstrate that lesions or inactivation of the BNST block the expression of freezing to the conditioning context, but not to an auditory conditional stimulus. These results reveal that the BNST has a critical role in the expression of contextual fear, but not fear to an auditory CS, and is therefore not the essential locus of compensation for fear learning in the absence of the BLA. [Copyright &y& Elsevier]

Abstract: Excitation of the mesocorticolimbic pathway, originating from dopaminergic neurons in the ventral tegmental area (VTA), may be important for the development of exaggerated fear responding. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. The functional role of the dopaminergic pathway connecting the VTA to the basolateral amygdala (BLA) in fear and anxiety has received little attention. In vivo microdialysis was performed to measure dopamine levels in the BLA of Wistar rats that received the dopamine D2 agonist quinpirole (1μg/0.2μl) into the VTA and were subjected to a fear conditioning test using a light as the conditioned stimulus (CS). The effects of intra-BLA injections of the D1 antagonist SCH 23390 (1 and 2μg/0.2μl) and D2 antagonist sulpiride (1 and 2μg/0.2μl) on fear-potentiated startle (FPS) to a light-CS were also assessed. Locomotor performance was evaluated by use of open-field and rotarod tests. Freezing and increased dopamine levels in the BLA in response to the CS were both inhibited by intra-VTA quinpirole. Whereas intra-BLA SCH 23390 did not affect FPS, intra-BLA sulpiride (2μg) inhibited FPS. Sulpiride’s ability to decrease FPS cannot be attributed to nonspecific effects because this drug did not affect motor performance. These findings indicate that the dopamine D2 receptor pathway connecting the ventral tegmental area and the basolateral amygdala modulates fear and anxiety and may be a novel pharmacological target for the treatment of anxiety. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders. [Copyright &y& Elsevier]

Abstract: Chronic stress and estrogens alter many forebrain regions in female rats that affect cognition. In order to investigate how chronic stress and estrogens influence fear learning and memory, we ovariectomized (OVX) female Sprague–Dawley rats and repeatedly injected them (s.c.) with 17β-estradiol (E, 10μg/250g or sesame oil vehicle, VEH). Concurrently, rats were restrained for 6h/d/21d (STR) or left undisturbed (CON). Rats were then fear conditioned with 4tone-footshock pairings and then after 1h and 24h delays, given 15tone extinction trials. Regardless of E treatment, chronic stress (VEH, E) facilitated freezing to tone during acquisition and extinction following a 1h delay, but not during extinction after a 24h delay. E did not influence freezing to tone during any phase of fear conditioning for either the control or chronically stressed rats, but did influence contextual conditioning that may have been carried predominately by the STR group. In the second experiment, we investigated “handling” influences on fear conditioning acquisition, given the disparate findings from the current study and previous work (). Female rats remained gonadally-intact since E did not influence tone fear conditioning. Indeed, brief daily handling (1–3m/d/21d) facilitated acquisition of fear conditioning in chronically stressed female rats, and either had no effect or slightly attenuated fear conditioning in controls. Thus, chronic stress impacts amygdala-mediated fear learning in both OVX- and gonadally-intact females as found previously in males, with handling significantly influencing these outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Fear conditioning is accepted as a useful experimental paradigm to investigate anxious disorders following stress. In this field it is important to understand the mechanisms underlying the extinction of conditioned fear. In the rat it has been shown that the amygdalar basolateral nucleus plays a crucial role in all memorization phases of this type of memory (acquisition, consolidation, retrieval, and also reconsolidation and extinction). Recent results show that both the substantia nigra and nucleus basalis magnocellularis, two sites strongly connected with the basolateral amygdala are also involved in the consolidation of contextual fear conditioning. The aim of the present work is to investigate if latter two sites, besides the basolateral amygdala, are also involved in the extinction of the conditioned fear response. The results show that tetrodotoxin-induced inactivation of post-extinction training of either site does not impair the extinction process, which instead is impaired by inactivation of the basolateral amygdala. Thus, the present results confirm previous ones which show that diverse memorization phases (post-acquisition consolidation, extinction, reconsolidation) may be sustained by different neural sites and circuits. [ABSTRACT FROM AUTHOR]

Abstract: Early in eyeblink classical conditioning, amygdala-dependent fear responding is reported to facilitate acquisition of the cerebellar-dependent eyeblink conditioned response (CR), in accord with the two-process model of conditioning (). In the current study, we predicted that the conditioned fear (e.g., freezing) observed during eyeblink conditioning may become autonomous of the eyeblink CR and amenable to further associative modification. Conditioned freezing was assessed during and following Pavlovian fear conditioning in Long-Evans rats that had or had not undergone eight prior sessions of eyeblink conditioning. The amplitude and frequency of the tone conditioned stimulus (CS) was held constant across both forms of conditioning. Following fear conditioning in Experiment 1, freezing to the tone CS, but not the context, was facilitated in rats that previously experienced CS-unconditioned stimulus (US) paired eyeblink conditioning. In Experiment 2, freezing immediately following each fear conditioning trial was enhanced in rats subjected to the antecedent eyeblink conditioning, indicating a faster acquisition rate. Finally, in Experiment 3, faster acquisition was seen only in those rats fear conditioned in the same context used for the prior eyeblink conditioning. Taken together, the data indicate that the conditioned fear associated with the context and CS as a result of eyeblink conditioning can be built upon or strengthened during subsequent learning. [ABSTRACT FROM AUTHOR]

Abstract: Animals develop robust learning and long lasting taste aversion memory once they experience a new taste that is followed by visceral discomfort. A large body of literature has supported the hypothesis that basolateral amygdala (BLA) plays a critical role in the acquisition and extinction of such conditioned taste aversions (CTA). Despite the evidence that BLA is crucially engaged during CTA training, it is unclear how BLA neural activity represents the conditioned tastes. Here, we incorporated a modified behavioral paradigm suitable for single unit study, one which utilizes a sequence of pulsed saccharin and water infusion via intraoral cannulae. After conditioning, we investigated BLA unit activity while animals experience the conditioned taste (saccharin). Behavioral tests of taste reactivity confirmed that the utilized training procedure produced reliable acquisition and expression of the aversion throughout test sessions. When neural activity was compared between saccharin and water trials, half of the recorded BLA units (77/149) showed differential activity according to the types of solution. 76% of those cells (29/38) in the conditioned group showed suppressed activity, while only 44% of taste reactive cells (17/39) in controls showed suppressed activity during saccharin trials (relative to water trials). In addition, the overall excitability of BLA units was increased as shown by altered characteristics of burst activity after conditioning. The changes in BLA activity as a consequence of CTA were maintained throughout test sessions, consistent with the behavioral study. The current study suggests that the neuronal activity evoked by a sweet taste is altered as a consequence of CTA learning, and that the overall change might be related to the learning induced negative affect. [Copyright &y& Elsevier]

Abstract: The basolateral amygdala complex (BLA) is involved in acquisition of contextual and auditory fear conditioning. However, the BLA is not a single structure but comprises a group of nuclei, including the lateral (LA), basal (BA) and accessory basal (AB) nuclei. While it is consensual that the LA is critical for auditory fear conditioning, there is controversy on the participation of the BA in fear conditioning. Hodological and neurophysiological findings suggest that each of these nuclei processes distinct information in parallel; the BA would deal with polymodal or contextual representations, and the LA would process unimodal or elemental representations. Thus, it seems plausible to hypothesize that the BA is required for contextual, but not auditory, fear conditioning. This hypothesis was evaluated in Wistar rats submitted to multiple-site ibotenate-induced damage restricted to the BA and then exposed to a concurrent contextual and auditory fear conditioning training followed by separated contextual and auditory conditioning testing. Differing from electrolytic lesion and lidocaine inactivation, this surgical approach does not disturb fibers of passage originating in other brain areas, restricting damage to the aimed nucleus. Relative to the sham-operated controls, rats with selective damage to the BA exhibited disruption of performance in the contextual, but not the auditory, component of the task. Thus, while the BA seems required for contextual fear conditioning, it is not critical for both an auditory-US association, nor for the expression of the freezing response. [Copyright &y& Elsevier]