Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli.

“…groups have shown that facilitating GABAergic transmission with the GABA-A agonist muscimol in the BLA reduces fear expression (Blair et al, 2005; Muller et al, 1997; Muller and Fendt, 2006), but this simply confirms lesion studies showing that BLA is essential for expression of conditioned fear.”

“However, this seems unlikely, because inactivation of the BASOLATERAL AMYGDALA (BLA) with the GABA A (γ-aminobutyric acid, type A) receptor agonist muscimol prevents the acquisition of fear conditioning, as well as the expression of fear memory, 24 hours after training when rats are tested drug-fre”

“Third, the temporal constraints of PET require peau and Davis, 1995; Muller et al., 1997; but see Kim that scans be averaged over both CS2 and non-CS and Davis, 1993b).”

“Reduced fear expression with BLA inactivation was expected, and agrees with previous inactivation studies (Muller et al., 1997; Maren and Holt, 2004).”

“[164] Muller J, Corodimas KP, Fridel Z, LeDoux JE.”

“Supporting a functional role for inhibitory transmission in fear conditioning, GABA A receptor activation reduces the acquisition of fear learning (Muller et al., 1997; Wilensky et al., 1999).”

“Reversible inactivation of LA during conditioning was found to prevent the acquisition of conditioned fear responses (275, 322, 527), and animals with excitotoxic lesions of the BLA could learn normal contextual fear but showed substantial forgetting 30 days after training compared with intact controls (382).”

“Conversely, activation of GABA-A receptors in LA impairs acquisition of conditioned fear (Muller et al., 1997; Wilensky et al., 1999) and fear conditioning is associated with reduced BLA levels of GABA (Stork et al., 2002) and mRNA for GABA-synthesizing enzymes (Pape and Stork, 2003; Heldt and…”

“Similarly, reversible inactivation of neurons in BLA prior to fear conditioning, via infusing the γ-aminobutyric acid (GABAA) receptor agonist muscimol, blocks the acquisition of conditioned fear, while amygdalar muscimol infusions (prior to retention testing) in previously fear conditioned rats impair the expression…”

“…with the GABA agonist muscimol during conditioning impairs the acquisition of auditory CS-elicited fear responses (Helmstetter and Bellgowan 1994; Muller et al. 1997; Wilensky et al. 1999, 2000), showing that neural activity in LA during conditioning is required for this type of fear learning to…”

“As shown in Figure 7, this delayed 1990) or the GABA agonist muscimol (Muller et al., 1997)signal was not present prior to conditioning.”

“Next, we used a lower concentration than that used in many other studies (Helmstetter and Bellgowan, 1994; Sanders and Shekhar, 1995; Muller et al., 1997; Schafe and LeDoux, 2000; Wilensky et al., 2000; Bahar et al., 2003), including some that specifically investigate spread issues (Edeline et al.,…”

“Similarly, reversible inactivation of the BLA prevents the acquisition and expression of conditioned fear (Helmstetter and Bellgowan, 1994; Muller et al., 1997), suggesting a large degree of overlap between the subnuclei of the amygdala.”

“Reversible inactivation of the BLA prior to training blocks the acquisition of fear conditioning (Miserendino et al. 1990; Maren et al. 1996b; Muller et al. 1997; Poremba and Gabriel 1999), and pretesting inactivation of the BLA prevents the expression of fear memories (Maren et al.”

“Both functional inactivation and receptor antagonism in the BLA before conditioning result in acquisition deficits, although the same manipulations made immediately after conditioning have no effect (Campeau et al., 1992; Fanselow and Kim, 1994; Helmstetter and Bellgowan, 1994; Maren et al., 1996b; Muller et al., 1997…”

“Many BLA-dependent behaviors are driven by discrete sensory stimuli that possess affective salience (Selden et al., 1991; Uwano et al., 1995; Davis, 1997; Muller et al., 1997).”

“Consistent with the anatomical data, lesioning or functionally inactivating the LA prior to training has consistently been observed to cause deficits in fear conditioning (LeDoux et al., 1990b; Helmstetter and Bellgowan, 1994; Campeau and Davis, 1995b; Muller et al., 1997; Wilensky et al., 1999; Amorapanth et al., 200…”

“Moreover, reversible inactivation of the BLA (Helmstetter and Bellgowan, 1994; Muller et al., 1997) or intra-BLA infusion of NMDA receptor antagonists (Miserendino et al.”

“Further, functional inactivation of LA and B disrupts fear conditioning (Helmstetter and Bellgowan 1994; Muller et al. 1997; Wilensky et al. 2000).”

“Similarly, inactivating LA neurons prevents fear expression (Helmstetter and Bellgowan, 1994; Maren et al., 2001; Muller et al., 1997).”

“These studies show that inactivation of the LA disrupts learning in a dose-dependent wa”

“Particularly important are findings that administration of drugs that impair Pavlovian fear conditioning when administered before training, such as the GABAA agonist muscimol or the NMDA receptor antagonist AP-5 (Liang et al., 1994; Maren et al., 1996b; Muller et al., 1997; Wilensky et al., 1999), impairs memory conso…”

“During the context extinction test, rats in the BLA group exhibited a severe deficit in freezing, which replicates previously reported data (Helmstetter & Bellgowan, 1994; Muller et al., 1997).”

“Moreover, the BLA has larger amounts of benzodiazepine/GABAA receptors than any other amygdala nucleus (Niehoff and Kuhar, 1983), explaining why the infusion of benzodiazepines or GABAA agonists in the BLA reduced fear conditioning and anxiety (Scheel-Kruger and Petersen, 1982; Petersen et al., 1985; Muller et al., 19…”

“[55] Muller J, Corodimas KP, Fridel Z, LeDoux JE.”

“To overcome these problems, pharmacological inactivation has been used to test the roles of various structures in fear acquisition, expression and extinction (Helmstetter & Bellgowan, 1994; Muller et al., 1997; Wilensky et al., 1999; Corcoran & Maren, 2001; Corcoran et al., 2005).”

“Concerning the conditioned freezing responses, of the above mentioned sites only BLA has been investigated by means of the reversible inactivation technique and this only during acquisition and retrieval (Helmstetter, 1992; Fanselow and Kim, 1994; Muller et al., 1997).”

“…of conditioned fear responses and underscore the importance of the amygdala as a critical target for the effects of GABAA and BZ receptor agonists (Brioni et al, 1989; Tomaz et al, 1993; Helmstetter and Bellgowan, 1994; Dickinson-Anson and McGaugh, 1997; Muller et al, 1997; Da Cunha et al, 1999).”

“BLA drives conditioned freezing through its projections to the central nucleus of the amygdala (LeDoux et al., 1988; Muller et al., 1997).”

“For example, LA neurons exhibit robust increases in activity (ie, neural plasticity) in response to the CS throughout conditioning (Maren and Quirk, 2004), and pre-training inactivation of the amygdala using muscimol leads to a disruption in longterm fear memory (Muller et al, 1997).”

“These results are consistent with those of previous studies, including work using intra-amygdala administration of AP5, in which AP5 impaired Pavlovian fear conditioning if given before, but not if given immediately after, training (Helmstetter and Bellgowan, 1994; Maren et al., 1996b; Muller et al., 1997).”

“Muscimol has proved to be a reliable agent for temporarily inactivating a number of brain structures including the amygdala (Helmstetter and Bellgowan, 1994; Muller et al., 1997) and hippocampus (Bellgowan and Helmstetter, 1995; Mao and Robinson, 1998).”

“The involvement of NMDA and GABAA receptors in conditioned fear response has been reported by intra-BLA infusion of NMDA receptor antagonists and the GABAA receptor agonist muscimol (Miserendino et al., 1990; Fanselow and Kim, 1994; Helmstetter and Bellgowan, 1994; Maren et al., 1996; Muller et al., 1997).”

“These results indicate that amygdalar lesions and muscimol infusions used in the present study were comparably effective to those used in fearconditioning studies (29, 30).”

“Substantial evidence also suggests that the BLA is involved in the acquisition and retention of Pavlovian contextual fear conditioning (CFC) (Helmstetter and Bellgowan, 1994; Maren et al., 1996; Muller et al., 1997; Vazdarjanova and McGaugh, 1998).”

“…extinction of conditioned memories through connections to the amygdala, which is the known output structure for the expression of conditioned fear (Muller et al., 1997; Wilensky et al., 2006) and is required for cue-induced reinstatement of cocaine-seeking behavior (Meil and See, 1997; McLaughlin…”

“LA is required for the expression of both aversive reactions and actions (Muller et al., 1997; Poremba and Gabriel, 1999; Amorapanth et al., 2000), as both categories of behavior require the predictive information encoded by LA neurons.”

“Inactivation of the BLA with muscimol produces deficits in the acquisition and expression of contextual fear conditioning (Helmstetter and Bellgowan, 1994; Muller et al., 1997), and intra-BLA infusions of NMDA receptor antagonists produce impairments in both first-order (Miserendino et al.”

“The BLC is also involved in the learning and retention of Pavlovian contextual fear conditioning (CFC), although the precise nature of the involvement remains controversial (Helmstetter and Bellgowan, 1994; Maren et al., 1996a,b; Muller et al., 1997; Maren, 1998; Vazdarjanova and McGaugh, 1998).”

“Similarly, previous experiments have shown that muscimol infusions into BLA temporarily impair fear conditioning (Helmstetter and Bellgowan, 1994; Muller et al., 1997; Wilensky et al., 2002; Wilensky et al., 2006).”

“…blockade of fear learning after pharmacological manipulation in the amygdala (Miserendino et al., 1990; Campeau et al., 1992; Maren et al., 1996b; Muller et al., 1997; Wilensky et al., 2000), suggest that the BLC is a site of plasticity and storage of emotional information (Fanselow and LeDoux,…”

“A similar pattern of results has been obtained with muscimol infusion into the amygdala (Helmstetter and Bellgowan, 1994; Muller et al., 1997).”

“20μl/side)[56,57] in the rAmy-ACC either pre-training or 24 hours later before the expression test (Fig.”

“Typically, muscimol is used in doses that cause inactivation of the area (Helmstetter & Bellgowan, 1994; Muller et al., 1997; Wilensky et al., 1999).”

“…of conditioned fear responses and underscore the importance of the amygdala as a critical target for the effects of GABAA and BZ receptor agonists (Brioni et al, 1989; Tomaz et al, 1993; Helmstetter and Bellgowan, 1994; Dickinson-Anson and McGaugh, 1997; Muller et al, 1997; Da Cunha et al, 1999).”

“establishing and remembering cue– shock associations (Muller et al. 1997).”

“This procedure has been valuable in determining the role of the amygdala and hippocampus in fear conditioning (Helmstetter and Bellgowan, 1994; Muller et al., 1997; Holt and Maren, 1999; Wilensky et al., 1999, 2000).”

“This possibility was considered (Pascoe and Kapp, 1985) but later abandoned as more and more data implicated the LA as the critical storage site (Campeau et al., 1992; Quirk et al., 1995; Muller et al., 1997; for review, see LeDoux, 2000).”

“…contextual fear memory Through its direct excitatory projections, the VH may regulate the neuralactivityofthemPFCandamygdala,whichisnecessaryfortherecallof contextual fear memory (Helmstetter and Bellgowan, 1994; Muller et al., 1997; Corcoran and Quirk, 2007; Goshen et al., 2011; Zhu et al., 2014).”

“The direct thalamic path to the Emotional memory and psychopathology J. E. LeDoux and J. Muller 1721 0 25 50 75 100 per cent freezing Unop • HPC • Amyg • 0 25 50 75 100 Lesion: Saline M u s c i m o l † † Infusion: 0 25 50 75 100 Lesion: Unop ° ACx ° HPC • MG ° Amyg • per cent freezing Saline Muscimol Muscimol † † Infu…”

“Although muscimol infusions have been utilized by numerous investigators [16,17], a recent study demonstrated that anxiety is reduced following prefrontal muscimol infusions in nonconditioned animals without having any effect on the cardiovascular stress response [18].”

“Neurotransmission in this pathway plays an important part in emotional learning and memory because fear conditioning is blocked by microinfusion of NMDA receptor antagonist (Miserendino et al., 1990) or GABAA receptor agonist muscimol into the BLA (Muller et al., 1997).”

“These studies have confirmed an important role for the BLA in both the acquisition and expression of conditional fear (Helmstetter and Bellgowan, 1994; Muller et al., 1997; Wilensky et al., 1999).”

“Studies in rodents suggested an involvement of the amygdala in learning associations between stimuli and aversive outcomes: rats with amygdala lesions show impairments in aversive association learning, but no effect of lesions on appetitive association learning (Cahill and McGaugh, 1990); infusion of muscimol in the a…”

“This is the putative site of plasticity mediating the acquisition of fear learning (LeDoux et al. 1990a; Quirk et al. 1995; McKernan and Shinnick-Gallagher 1997; Muller et al. 1997; Rogan et al. 1997).”

“In fact, both acquisition and retention of fear conditioning occur in the lateral nucleus, where electrolytic and excitotoxic lesions, as well as pharmacological blockade, prevent acquisition and expression of fear conditioning (Campeau and Davis 1995; Muller et al. 1997; LeDoux 2000; Gale et al. 2004).”

“This depression is consistent with the well-accepted view that activity in the BLA is critical for the expression of conditioned fear responses (Helmstetter and Bellgowan 1994; Muller et al. 1997; Lee and Kim 1998; Lee et al. 2001; Maren et al. 2001; Wilensky et al. 2006).”

“At the very least the basal or lateral nuclei are implicated, as selective muscimol injections (Muller et al. 1997) or blockade of NMDA receptors (Lee and Kim 1998) in these nuclei disrupt both the acquisition and expression of the conditioned response.”

“…cues can be disrupted by treatments that interfere with basolateral amygdala function (e.g., Fanselow and Kim 1994; Helmstetter and Bellgowan 1994; Muller et al. 1997; Goosens and Maren 2001, 2003; Rodrigues et al. 2001; Wallace and Rosen 2001) our results are not wholly without precedent.”

“On the one hand, reduced inhibitory control in the amygdala is typically expected to enhance long-term potentiation (LTP) and to facilitate Pavlovian fear conditioning, whereas enhanced inhibition has opposite effects (Muller et al. 1997; Wilensky et al. 1999).”

“We found that bilateral inactivation of the amygdala prevented learning in delay conditioning, consistent with the literature (Muller et al., 1997).”