Abstract: The authors recently showed that extinction of auditory fear conditioning leads to potentiation of tone-evoked activity of neurons in the infralimbic (IL) subregion of the medial prefrontal cortex, suggesting that IL inhibits fear after extinction (M. R. Milad, & G. J. Quirk, 2002). In support of this finding, pairing conditioned tones with brief (300-ms) electrical stimulation of IL reduces conditioned freezing. The present study showed that IL stimulation inhibits freezing if given 0.1 s after tone onset (the latency of tone-evoked responses) but has no effect if given either 1 s before or 1 s after tone onset. This suggests that IL gates the response of downstream structures such as the amygdala to fear stimuli.

Abstract: Anxiety induced by 2 types of predictable and unpredictable aversive stimuli, an unpleasant shock or a less aversive airblast to the larynx, were investigated in a between-group design. Participants anticipated predictable (signaled) or unpredictable (not signaled) aversive events, or no aversive event. Unpredictable, relative to predictable, contexts potentiated the startle reflex in the shock group but not in the airblast group. These data suggest that unpredictability can lead to a sustained level of anxiety only when the pending stimulus is sufficiently aversive. Because predictable and unpredictable danger may induce different types of aversive responses, the proposed design can serve as a useful tool for studying the neurobiology and psychopharmacology of fear and anxiety.

Abstract: The authors compared the effects of pharmacological inactivation of the dorsal hippocampus (DH) or ventral hippocampus (VH) on Pavlovian fear conditioning in rats. Freezing behavior served as the measure of fear. Pretraining infusions of muscimol, a GABAA receptor agonist, into the VH disrupted auditory, but not contextual, fear conditioning; DH infusions did not affect fear conditioning. Pretesting inactivation of the VH or DH did not affect the expression of conditional freezing. Pretraining electrolytic lesions of the VH reproduced the effects of muscimol infusions, whereas posttraining VH lesions disrupted both auditory and contextual freezing. Hence, neurons in the VH are importantly involved in the acquisition of auditory fear conditioning and the expression of auditory and contextual fear under some conditions. An abundance of evidence indicates that the hippocampus is importantly involved in associative learning and memory (Anagnostaras, Gale, & Fanselow, 2001; Douglas, 1967; Eichenbaum,

Abstract: This experiment examined the effect of repeated corticosterone injections on anxiety and depression-like behavior in male and female rats. Rats received either corticosterone or vehicle injections for 21 consecutive days prior to behavioral testing in the forced swim, open-field, and predator odor tests. The corticosterone injections significantly increased depression-like behavior in the forced swim test in both male and female rats but had no significant effect on anxiety in the open-field test. In the predator odor test, the corticosterone injections significantly increased a subset of defensive behaviors in the male rats. These results suggest that repeated exposure to corticosterone increases depression-like behavior, with some effects on anxiety, and that male rats may be more affected than female rats by this manipulation.

Abstract: Recent studies provide evidence for an interaction between a declarative memory system, dependent on the medial temporal lobe (MTL), and a habit memory system, dependent on the basal ganglia. Using functional MRI, the authors studied this interaction when 1 system was compromised by neurological disease. Neural activity when performing a habit-learning task was compared in normal controls and subjects with Parkinson's disease (PD). Patients with PD showed less activation in the caudate nucleus and greater activation in a region of prefrontal cortex that has been associated with explicit memory retrieval. Patients with PD also showed activation of the MTL during the weather-prediction task. These findings are consistent with an interaction between memory systems of the MTL and the striatum.

Abstract: The purpose of the present study was to gain a deeper understanding of the role of the basal ganglia in learning and memory by examining learning strategies among patients with basal ganglia dysfunction. Using a probabilistic category learning task (the "weather prediction" task) previously shown to be sensitive to basal ganglia function, the authors examined patterns of performance during learning and used mathematical models to capture different learning strategies. Results showed that patients with Parkinson's disease exhibit different patterns of strategy use. Specifically, most controls initially used a simple, but suboptimal, strategy that focused on single-cue-outcome associations; eventually, however, most controls adopted a more complex, optimal learning strategy, integrating single-cue associations to predict outcomes for multiple-cue stimuli. In contrast, the majority of individuals with Parkinson's disease continued to rely on simple single-cue learning strategies throughout the experiment.

Abstract: The authors measured the effects of centrally infused peptides on social approach behaviors in goldfish (Carassius auratus), a social teleost. Vasotocin (VT) inhibited approach responses toward the visual stimuli of conspecifics in the absence of aggressive or sexual olfactory contextual cues in males, and a V1 receptor antagonist stimulated such responses, at least in males that were not highly social in baseline conditions, as did isotocin (IT). In the absence of social stimuli, VT did not affect activity, therefore indicating that the inhibition was not the result of nonspecific effects on arousal or motor functioning. These experiments indicate that VT and IT induce opposite effects on social approach responses in male goldfish and that endogenous VT, at least, is associated with levels of sociality.

Abstract: The authors hypothesized that insulin and leptin, hormones that convey metabolic and energy balance status to the central nervous system (CNS), decrease the reward value of food, as assessed by conditioned place preference (CPP). CPP to high-fat diet was blocked in ad-lib fed rats given intraventricular insulin or leptin throughout training and test or acutely before the test. Insulin or leptin given only during the training period did not block CPP. Thus, elevated insulin and leptin do not prevent learning a food's reward value, but instead block its retrieval. Food-restricted rats receiving cerebrospinal fluid, insulin, or leptin had comparable CPPs. Results indicate that the CNS roles of insulin and leptin may include processes involving memory and reward.

Abstract: This study examined the participation of the medial amygdala (MeA) in unconditioned fear. Rats received ibotenic acid lesions in the MeA or central amygdala (CeA) prior to cat-odor exposure. MeA-lesioned rats exhibited a significant reduction in freezing duration and made frequent contact with a cloth containing cat odor. In contrast, CeA lesions had no significant effects on unconditioned fear. The freezing reduction produced by MeA lesions was not due to a performance deficit because MeA-lesioned rats, unlike CeA-lesioned rats, were capable of freezing in postshock test intervals. Furthermore, MeA lesions did not alter olfactory function and general locomotor activity. Results demonstrate that the MeA plays a major role in modulating predator odor-induced unconditioned fear.

Abstract: Although testosterone (T) may decrease anxiety and enhance cognitive performance, its mechanisms are not well understood The authors hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced, nonaromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase reduced metabolite 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol administration should produce similar behavioral effects concomitant with elevating T metabolites in the hippocampus Gonadectomized male rats administered T, DHT, or 3alpha-diol via Silastic capsules or intrahippocampal infusions had greater analgesia (tail flick, paw lick), less anxiety behavior (plus-maze, open field, defensive freezing), and better learning (inhibitory avoidance) compared with vehicle control rats Only 3alpha-diol levels in the hippocampus were consistently elevated in conjunction with these behavioral effects

Abstract: Experimental data and computational models suggest that blockade of muscarinic cholinergic receptors impairs paired-associate learning and increases proactive interference (E. DeRosa & M. E. Hasselmo, 2000; M. E. Hasselmo & J. M. Bower, 1993). The results presented here provide evidence in humans supporting these hypotheses. Young healthy subjects first learned baseline word pairs (A-B) and, after a delay, learned additional overlapping (A-C) and nonoverlapping (D-E) word pairs. As predicted, when compared with subjects who received the active placebo glycopyrrolate (4 microg/kg) and subjects who were not injected, those who received scopolamine (8 microg/kg) showed (a) overall impairment in new word paired-associate learning, but no impairment in cued recall of previously learned associates; and (b) greater impairment in learning overlapping (A-C) compared with nonoverlapping (D-E) paired associates.

Abstract: The relationship between a social partner's stress status and the social buffering effect was examined in adult male Wistar rats. Fear-conditioned rats were exposed to the same context along with either a shocked or nonshocked conspecific partner. Changes in body temperature and behavioral responses were monitored in order to compare the effects of social buffering, and the Fos protein in the paraventricular nucleus was immunostained. The presence of the partner rat attenuated stress-induced hyperthermia, as well as behavioral responses and Fos expression in response to the fearful context, and nonshocked partners were more effective than shocked partners. These findings suggest that the social buffering effect depends on the stress status of the accompanying conspecific animal.

Abstract: The neurobiology of hand preferences in nonhuman primates is poorly understood. In this study, the authors report the 1st evidence of an association between hand preference and precentral gyrus morphology in chimpanzees (Pan troglodytes). Hand preferences did not significantly correlate with other asymmetric brain regions associated with language functions in humans including the planum temporale and frontal operculum. The overall results suggest that homologous regions of the motor cortex control hand preferences in humans and apes and that these functions evolved independently of left-hemisphere specialization for language and speech.

Abstract: Odors seem to be perceived differently when presented ortho- or retronasally. In this study, stimuli of controlled concentration and duration were applied in either the anterior nasal cavity or epipharynx by means of air-dilution olfactometry. Stimulus concentration was monitored in the olfactory cleft. In Experiment 1, odor thresholds to a food (chocolate) and a nonfood (lavender) odor were lower for orthonasal, compared with retronasal, stimulation. In Experiment 2, intensity ratings to suprathreshold odor concentrations were significantly higher for orthonasal than for retronasal stimulation with hydro- hydrogen sulfide, but not phenyl ethyl alcohol. Accordingly, amplitudes and latencies of olfactory event-related gen potentials to retronasal stimuli were found to be smaller and prolonged, respectively. This indicates differential processing of olfactory stimuli presented through the retronasal or orthonasal routes. )

Abstract: Lactating females that fiercely protect offspring exhibit decreased fear and anxiety. The authors tested whether decreased corticotropin-releasing factor (CRF), an activator of fear and anxiety, plays a functional role in maternal aggression. Intracerebroventricular (icv) injections of CRF (1.0 and 0.2 microg, but not 0.02 microg) significantly inhibited maternal aggression but not other maternal behaviors. The CRF antagonist D-Phe-CRF(12-41) had no effect. Maternal aggression and icv CRF (0.2 microg) induced Fos in 11 of the same regions, including the lateral and medial septum, the bed nucleus of the stria terminalis, the medial and central amygdala, the periaqueductal gray, the dorsal raphe, and the locus coeruleus. These findings suggest that decreased CRF is necessary for maternal aggression and may act by altering brain activity in response to an intruder.

Abstract: Sixteen participants viewed a videotaped tour of 4 houses that highlighted a series of objects and their spatial locations. Participants were tested for memory of object, spatial, and temporal-order information while undergoing functional magnetic resonance imaging. Preferential activation was observed in the right parahippocampal gyrus during the retrieval of spatial-location information. Retrieval of contextual information (spatial location and temporal order) was associated with activation in the right dorsolateral prefrontal cortex. In bilateral posterior parietal regions, greater activation was associated with processing of visual scenes regardless of the memory judgment. These findings support current theories positing roles for frontal and medial temporal regions during episodic retrieval and suggest a specific role for the hippocampal complex in the retrieval of spatial-location information.

Abstract: Recent studies have identified putative cellular correlates of stress-induced amygdalar plasticity underlying anxiety-like behavior. Chronic immobilization stress (CIS), but not chronic unpredictable stress (CUS), has been reported to induce dendritic remodeling in the basolateral amygdala (BLA). The BLA is also important for consolidation of anxiety in the elevated plus-maze, which is manifested as increased open-arm avoidance on reexposure to the maze. The authors found that CIS, unlike CUS, facilitated anxiety-like behavior in the plus-maze, and this occluded further increase in anxiety when CIS rats were reexposed to the maze 72 hr after the first trial. However, both CUS and control rats exhibited consolidation between trials. Thus, consolidation of anxiety may share common cellular mechanisms that also underlie chronic stress-induced structural plasticity in the amygdala.

Abstract: The relative contribution of left and right amygdalae in the acquisition and retention of fear conditioning was investigated in rats. Pretraining bilateral electrolytic lesions blocked the acquisition of conditioned fear to tone and context, whereas unilateral lesions induced partial impairments with no left-right amygdala differences. In contrast, posttraining bilateral and unilateral lesions produced significant deficits in the retention of conditioned fear to tone and context. Although no left-right difference was observed to tone, the right amygdala lesions generated greater deficits in contextual fear than the left amygdala lesions. These results indicate that fear conditioning is partially disrupted with unilateral amygdalar lesions, but that the right amygdala has greater involvement than the left amygdala when conditioning occurs under a normal brain state.

Abstract: The nucleus accumbens (NAc) plays a role in conditioned place preference (CPP). The authors tested the hypothesis that inhibition of mitogen-activated protein kinases (MAPKs) would inhibit NAcamphetamine-produced CPP. Results confirmed that NAc amphetamine increased levels of the MAPK extracellular signal-regulated kinase (ERK). In CPP studies, NAc injections (0.5 l per side) of the ERK inhibitor PD98059 (1.0 –2.5 g) or the p38 kinase inhibitor SB203580 (15–500 ng) dose dependently impaired CPP. The c-Jun-N-terminal kinase (JNK) inhibitor SP600125 (1.0 –2.5 g) failed to block the CPP effect. The drugs did not block amphetamine-induced motor activity. Results suggest that ERK and p38, but not JNK, MAPKs may be necessary for the establishment of NAc amphetamine-produced CPP and may also mediate other forms of reward-related learning dependent on NAc.

Abstract: The authors investigated whether corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) is a critical component of the neural circuitry mediating conditioned defeat. In this model, hamsters that have experienced social defeat subsequently display only submissive-defensive agonistic behavior instead of territorial aggression. Conditioned defeat was significantly reduced following infusion of the CRF receptor antagonist D-Phe CRF((12-41)) into the BNST but not into the CeA. In another experiment, hamsters given unilateral lesions of the CeA and infusions of D-Phe CRF((12-41)) into the contralateral BNST displayed significantly less submissive behavior than did controls. These data suggest that CRF acts within a neural circuit that includes the amygdala and the BNST to modulate agonistic behavior following social defeat.

Abstract: The authors examined the effects of activity wheel running (AWR) and propranolol on contextual fear conditioning (CFC) and messenger RNA (mRNA) for galanin (GAL) in the locus coeruleus (LC) and brain-derived neurotrophic factor (BDNF) in the hippocampal formation (HF) in rats. Freezing behavior during the testing session of the CFC protocol was elevated in the AWR-placebo group compared to sedentary-placebo and AWR-propranolol groups. AWR increased GAL mRNA in the LC. CFC increased BDNF mRNA in the HF. These results suggest that exercise enhances CFC and that antagonism of the beta-adrenoreceptors attenuates this effect. The exercise-related induction of GAL gene expression in the LC may influence noradrenergic transmission to facilitate CFC.

Abstract: These experiments tested whether nucleus accumbens muscarinic or nicotinic acetylcholine receptor activation is required for rats to learn to lever press for sucrose. Muscarinic blockade with scopolamine (1.0 microg/side or 10.0 microg/side), but not nicotinic antagonism with mecamylamine (10.0 microg/side), inhibited learning and performance when applied to the core or shell. Further experiments showed that acute accumbens scopolamine treatment increased locomotor activity and reduced sucrose consumption. However, microanalyses of behavioral events in the instrumental chamber revealed that reductions of lever press performance during muscarinic blockade were not due to gross motor dysfunction. Accumbens core scopolamine was subsequently shown to reduce the amount of work rats would expend under a progressive ratio paradigm. These novel results implicate nucleus accumbens muscarinic receptors in the modulation of appetitive learning, performance, and motivation for food.

Abstract: Neuroticism and extraversion are personality traits associated with negative and positive mood states, respectively, confounding trait and state factors that may affect brain responses to emotional stimuli. The authors dissociated these factors using fMRI and the emotional Stroop attention task: Anterior cingulate (AC) response to positive stimuli varied as a function of personality trait, but not mood state, whereas AC response to negative stimuli varied as a function of mood state, but not personality trait. Negative mood, but not personality trait, also increased the functional connectivity between AC and other regions. Variance in AC activation can thus be ascribed to an intersubject variable (extraversion) when responding to positive stimuli and an intrasubject variable (mood) when responding to negative stimuli. The former may explain stable differences between extraverts and introverts. The latter may provide an adaptive mechanism to expand an individual's dynamic range in response to potentially dangerous or threatening stimuli.

Abstract: This study tested whether chronic oral estrogen could improve memory and alter neural plasticity in the hippocampus and neocortex of middle-aged female mice. Ovariectomized C57BL/6 mice were administered 1,000, 1,500, or 2,500 nM 17beta-estradiol in drinking water for 5 weeks prior to and during spatial and object memory testing. Synaptophysin, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels were then measured in hippocampus and neocortex. The medium dose impaired spatial reference memory in the radial-arm maze, whereas all doses improved object recognition. The high dose increased hippocampal synaptophysin and NGF levels, whereas the medium dose decreased these neocortical levels. The high dose decreased neocortical BDNF levels. These data suggest that chronic oral estrogen selectively affects memory and neural function in middle-aged female mice.

Abstract: The acoustic startle reflex (ASR) is potentiated during negative emotion, but attenuated during positive emotional experience. The modulation of the ASR by fear depends critically on the amygdala. The authors investigated ASR modulation to fearful, disgusting, pleasant, and neutral stimuli in 12 patients with unilateral damage to the anteromedial temporal lobe including the amygdala (6 left, 6 right), 1 patient with bilateral temporal lobe damage including the amygdala, and 12 comparison participants. Both groups with unilateral damage, as well as the subject with bilateral damage, showed a complete lack of ASR potentiation to both fear and disgust stimuli. The findings suggest that potentiation of the ASR by disgust and fear depends on the integrity of the anteromedial temporal lobe.

Abstract: Feather-pecking behavior in laying hens (Gallus gallus) may be considered a behavioral pathology, comparable to human psychopathological disorders. Scientific knowledge on the causation of such disorders strongly suggests involvement of the serotonergic (5-hydroxytryptamine; 5-HT) system in feather pecking. Previously, chicks from a high-feather-pecking (HFP) line were found to display lower 5-HT turnover levels than chicks from a low-feather-pecking (LFP) line (in response to acute stress; Y. M. van Hierden et al., 2002). The present study investigated whether low 5-HT neurotransmission modulates feather pecking. First, S-15535, a somatodendritic 5-HT1A autoreceptor agonist, was demonstrated to be an excellent tool for reducing 5-HT turnover in the forebrain of LFP and HFP chicks. Second, the most effective dose of S-15535 (4.0 mg/kg body weight) significantly increased severe feather-pecking behavior. The results confirmed the postulation that the performance of feather pecking is triggered by low 5-HT neurotransmission.

Abstract: Although it is known that there are fundamental personality differences in the behavioral responses to emotional stimuli, traits have scarcely been investigated in this context by means of functional imaging studies. To maximize the variance with respect to personality, the authors tested 12 control subjects and 12 subjects who had sadomasochistic experiences with respect to the relationship between J. A. Gray's (1970) personality dimensions, the behavioral approach system (BAS) and the behavioral inhibition system (BIS), and brain activity in regions of interest. The BIS was associated with activity in numerous brain areas in response to fear, disgust, and erotic visual stimuli, whereas few associations could he detected between the BAS and brain activity in response to disgust and erotic stimuli.

Abstract: Injection of the opioid receptor antagonist naloxone facilitated acquisition of fear to contextual and auditory conditioned stimuli (CSs) in Experiments 1A and 1B. Experiment 2 showed that prior conditioning to a distinctive context blocked conditioning to an auditory CS. Blocking of CS fear was prevented by administrations of naloxone or increases in footshock intensity. Blocking of CS fear was facilitated by decreases in footshock intensity in a naloxone-reversible manner. Experiment 3 showed that compound conditioning of two CSs, each previously and separately paired with shock, produced overexpectation of fear that was reversed by naloxone. These results are consistent with a role for opioid receptors controlling Pavlovian association formation by regulating the discrepancy ( V) described by R. A. Rescorla and A. R. Wagner (1972). Placed in a novel context (a distinctive chamber) and exposed to pairings of a discrete conditioned stimulus (CS) with brief but aversive footshock (unconditioned stimulus [US]), rats learn about this relation between the context, the CS, and US. They exhibit this learning when reexposed to either the CS or context in a diverse but correlated range of behavioral, endocrine, and autonomic reactions that include freezing, hypoalgesia, potentiated startle, corticosteroid release, and increased arterial blood pressure (Davis, 1992; Fanselow & LeDoux, 1999; LeDoux, 2000; Maren, 2001). The contents of this learning are commonly viewed in terms of the formation of excitatory associations between a representation of the context, the CS, and a fear motivational system aroused by the aversive US (Konorski, 1967; but see Bolles & Fanselow, 1980). Considerable evidence supports the view that these excitatory Pavlovian associations are mediated by glutamatergic neurotransmission in the amygdala. Specifically, this evidence suggests that activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala basolateral nucleus (ABl) detects the CS–US conjunction. This activation, in turn, initiates a variety of signal transduction cascades (e.g., Ca 2 and cyclic AMP-dependent signaling) to result in synaptic plasticity and the long-term representation of the CS–US association (for reviews, see Fanselow & LeDoux, 1999; Maren, 1996, 2001). Among the evidence consistent with this view are lesion data showing that ABl destruction abolishes fear conditioning (Campeau & Davis, 1995; Goosens & Maren, 2001; Sananes & Davis, 1992), neuropharmacological data showing that infusions of NMDA receptor antagonists prevent the acquisition of fear conditioning (e.g., Campeau, Miserendino, & Davis, 1992; Kim, DeCola, Landeira-Fernandez, & Fanselow, 1991; Miserendino, Sananes, Melia, & Davis, 1990), and electrophysiological data showing that fear conditioning produces synaptic plasticity in the ABl that is correlated with conditioned freezing (e.g., Rogan, Staubli, & LeDoux, 1997). Moreover, this NMDA-receptordependent plasticity is often further related to Hebb’s (1949) learning rule, which states that the increment in learning on a conditioning trial is a function of a constant, activity in a presynaptic neuron, and activity in a postsynaptic neuron.

Abstract: Fear conditioning has provided a useful model system for studying associative emotional learning, but the impact of healthy aging has gone relatively unexplored. The present study investigated fear conditioning across the adult life span in humans. A delay discrimination task was employed using visual conditioned stimuli and an auditory unconditioned stimulus. Awareness of the reinforcement contingencies was assessed in a postexperimental interview. Compared with young adult participants, middle-aged and older adults displayed reductions in unconditioned responding, discriminant conditioning, and contingency awareness. When awareness and overall arousability were taken into consideration, there were no residual effects of aging on conditioning. These results highlight the importance of considering the influence of declarative knowledge when interpreting age-associated changes in discriminative conditioned learning.