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Knowing when and where to express fear is essential to survival. Recent work in fear extinction paradigms reveals that the contextual regulation of fear involves a neural network involving the hippocampus, medial prefrontal cortex and amygdala. The amygdaloid basal nuclei (BA) receive convergent input from the ventral hippocampus (VH) and prelimbic (PL) prefrontal cortex, and may integrate VH and PL input to regulate fear expression. To examine the functional organization of this neural circuit, we used cellular imaging of c-fos expression in anatomically defined neuronal populations and circuit disconnections to identify the pathways involved in the contextual control of extinguished fear. Prior to behavioral testing, we infused a retrograde tracer into the amygdala to label BA-projecting neurons in VH and PL. Rats then underwent fear conditioning and extinction and were tested for their fear to the extinguished conditioned stimulus (CS) in either the extinction context or in another context; freezing behavior served as the index of conditional fear. CS presentation outside the extinction context renewed conditional freezing, and was associated with significantly more c-fos expression in BA-projecting neurons in the VH and PL than that induced by CS presentation in the extinction context. We next examined whether direct or indirect projections of VH to BA mediate fear renewal. Interestingly, disconnections of the VH from either the BA or PL eliminated renewal. These findings suggest that convergent inputs from both the ventral hippocampus and prelimbic cortex in the basal amygdala mediate the contextual control of fear after extinction.

After extinction of conditioned fear, memory for the conditioning and extinction experiences becomes context dependent. Fear is suppressed in the extinction context, but renews in other contexts. This study characterizes the neural circuitry underlying the context-dependent retrieval of extinguished fear memories using c-Fos immunohistochemistry. After fear conditioning and extinction to an auditory conditioned stimulus (CS), rats were presented with the extinguished CS in either the extinction context or a second context, and then sacrificed. Presentation of the CS in the extinction context yielded low levels of conditioned freezing and induced c-Fos expression in the infralimbic division of the medial prefrontal cortex, the intercalated nuclei of the amygdala, and the dentate gyrus (DG). In contrast, presentation of the CS outside of the extinction context yielded high levels of conditioned freezing and induced c-Fos expression in the prelimbic division of the medial prefrontal cortex, the lateral and basolateral nuclei of the amygdala, and the medial division of the central nucleus of the amygdala. Hippocampal areas CA1 and CA3 exhibited c-Fos expression when the CS was presented in either context. These data suggest that the context specificity of extinction is mediated by prefrontal modulation of amygdala activity, and that the hippocampus has a fundamental role in contextual memory retrieval.

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It is well known that emotions participate in the regulation of social behaviors and that the emotion displayed by a conspecific influences the behavior of other animals. In its simplest form, empathy can be characterized as the capacity to be affected by and/or share the emotional state of another. However, to date, relatively little is known about the mechanisms by which animals that are not in direct danger share emotions. In the present study, we used a model of between-subject transfer of fear to characterize the social interaction during which fear is transmitted, as well as the behavioral effects of socially transmitted fear. We found that (1) during social interaction with a recently fearconditioned partner, observers and demonstrators exhibit social exploratory behaviors rather than aggressive behaviors; (2) learning and memory in a shock-motivated shuttle avoidance task are facilitated in rats that underwent a social interaction with a partner that had been fear conditioned; and (3) a brief social interaction with a recently fearconditioned partner immediately before fear conditioning increases conditioned freezing measured on the next day. The observed effects were not due to a stress-induced increase in pain sensitivity or analgesia. Collectively, these data suggest that a brief social interaction with a cage mate that has undergone an aversive learning experience promotes aversive learning in an otherwise naïve animal. We argue that socially transferred fear is an adaptation that promotes defensive behavior to potentially dangerous situations in the environment.Human empathy can be defined as the ability to experience and share the thoughts and feelings of others (de Waal 2008). Obviously, this is a complex social phenomenon that, until recently, has received much attention from philosophers and psychologists rather than neuroscientists (Decety and Lamm 2006). However, in its simplest form, empathy can be characterized as the capacity to be affected by and/or share the emotional state of another (de Waal 2008). Tuning one's emotional state to that of another increases the probability of similar behavior, which thereby allows rapid adaptation to environmental challenges (Hatfield et al. 1994). This social adaptation may be particularly important for emotions that signal a potential danger, such as fear. Although one can learn about potentially harmful stimuli by directly experiencing an aversive event, observation or interaction with a conspecific in danger and/or in pain may also provide information about threats in the environment. There is a vast literature on learning about direct danger (Maren 2001) as well as sharing emotions through observation (see, e.g., Church 1959;Langford et al. 2006;Olsson and Phelps 2007). However, relatively little is known about the mechanisms by which animals that are not in a direct danger share emotions.We have recently designed an experimental rat model of between-subject transfer of emotional information (Knapska et al. 2006). In this model, rats are housed in pa...

The amygdala is a heterogeneous brain structure implicated in processing of emotions and storing the emotional aspects of memories. Gene activity markers such as c-Fos have been shown to reflect both neuronal activation and neuronal plasticity. Herein, we analyze the expression patterns of gene activity markers in the amygdala in response to either behavioral training or treatment with drugs of abuse and then we confront the results with data on other approaches to internal complexity of the amygdala. c-Fos has been the most often studied in the amygdala, showing specific expression patterns in response to various treatments, most probably reflecting functional specializations among amygdala subdivisions. In the basolateral amygdala, c-Fos expression appears to be consistent with the proposed role of this nucleus in a plasticity of the current stimulus-value associations. Within the medial part of the central amygdala, c-Fos correlates with acquisition of alimentary/gustatory behaviors. On the other hand, in the lateral subdivision of the central amygdala, c-Fos expression relates to attention and vigilance. In the medial amygdala, c-Fos appears to be evoked by emotional novelty of the experimental situation. The data on the other major subdivisions of the amygdala are scarce. In conclusion, the studies on the gene activity markers, confronted with other approaches involving neuroanatomy, physiology, and the lesion method, have revealed novel aspects of the amygdala, especially pointing to functional heterogeneity of this brain region that does not fit very well into contemporarily active debate on serial versus parallel information processing within the amygdala.

The memory of fear extinction is context dependent: fear that is suppressed in one context readily renews in another. Understanding of the underlying neuronal circuits is, therefore, of considerable clinical relevance for anxiety disorders. Prefrontal cortical and hippocampal inputs to the amygdala have recently been shown to regulate the retrieval of fear memories, but the cellular organization of these projections remains unclear. By using anterograde tracing in a transgenic rat in which neurons express a dendriticallytargeted PSD-95:Venus fusion protein under the control of a c-fos promoter, we found that, during the retrieval of extinction memory, the dominant input to active neurons in the lateral amygdala was from the infralimbic cortex, whereas the retrieval of fear memory was associated with greater hippocampal and prelimbic inputs. This pattern of retrieval-related afferent input was absent in the central nucleus of the amygdala. Our data show functional anatomy of neural circuits regulating fear and extinction, providing a framework for therapeutic manipulations of these circuits.gene expression | hippocampus | prefrontal cortex | learning and memory T here is an increasing interest in the neural mechanisms underlying extinction of learned fear, in part because fear extinction is a useful model for exposure-based therapies for the treatment of human anxiety disorders, such as phobias and posttraumatic stress disorder (1). During fear extinction, a previously conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US), a procedure that induces a progressive decrease in the magnitude and probability of learned fear responses, including freezing behavior. However, extinction does not erase the original fear memory; rather, it promotes the formation of a new inhibitory memory that reduces fear to the CS (2). Extinguished fear is highly context dependent, insofar as CS presentation outside the extinction context results in the recovery of the previously conditioned fear response, a phenomenon known as fear renewal (3). The return of fear after extinction is a considerable challenge for the efficacy of exposure-based therapies (4). Therefore, identification of brain structures and neuronal circuits selectively implicated in extinction vs. renewal of fear is of great importance.Owing to substantial progress toward understanding the neural mechanisms underlying the context specificity of fear extinction, there is now a general consensus that, for auditory fear conditioning, extinction involves three main structures: the amygdala, hippocampus (HIPP), and prefrontal cortex (PFC) (2, 5-8). However, the neuronal interactions between these structures that underlie contextual retrieval of fear memory after extinction remain to be elucidated. This problem is further complicated by the fact that neither the amygdala nor the PFC is a homogeneous structure. Among the substructures of the amygdala, the central, basal, and lateral nuclei (Ce, Ba, and La, respectively) have been impl...

Empathy is a phenomenon often considered dependent on higher-order emotional control and an ability to relate to the emotional state of others. It is, by many, attributed only to species having well-developed cortical circuits capable of performing such complex tasks. However, over the years, a wealth of data has been accumulated showing that rodents are capable not only of sharing emotional states of their conspecifics, but also of prosocial behavior driven by such shared experiences. The study of rodent empathic behaviors is only now becoming an independent research field. Relevant animal models allow precise manipulation of neural networks, thereby offering insight into the foundations of empathy in the mammalian brains. Here we review the data on empathic behaviors in rat and mouse models, their neurobiological and neurophysiological correlates, and the factors influencing these behaviors. We discuss how simple rodent models of empathy enhance our understanding of how brain controls empathic behaviors.