The cortico–basal ganglia–thalamo–cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1–4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico–basal ganglia–thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico–basal ganglia–thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.
A prominent feature of fear memories and anxiety disorders is that they endure across extended periods of time. Here, we examine how the severity of the initial fear experience influences incubation, generalization, and sensitization of contextual fear memories across time. Adult rats were presented with either five, two, one, or zero shocks (1.2 mA, 2 sec) during contextual fear conditioning. Following a recent (1 d) or remote (28 d) retention interval all subjects were returned to the original training context to measure fear memory and/or to a novel context to measure the specificity of fear conditioning. Our results indicate rats that received two or five shocks show an "incubation"-like enhancement of fear between recent and remote retention intervals, while single-shocked animals show stable levels of context fear memory. Moreover, when fear was tested in a novel context, 1 and 2 shocked groups failed to freeze, whereas five shocked rats showed a time-dependent generalization of context memory. Stress enhancement of fear learning to a second round of conditioning was evident in all previously shocked animals. Based on these results, we conclude that the severity or number of foot shocks determines not only the level of fear memory, but also the time-dependent incubation of fear and its generalization across distinct contexts.
Development and sex differentiation impart an organizational influence on the neuroanatomy and behavior of mammalian species. Prior studies suggest that brain regions associated with fear motivated defensive behavior undergo a protracted and sex-dependent development. Outside of adult animals, evidence for developmental sex differences in conditioned fear is sparse. Here, we examined in male and female Long-Evans rats how developmental age and sex affect the long-term retention and generalization of Pavlovian fear responses. Experiments 1 and 2 describe under increasing levels of aversive learning (three and five trials) the long-term retrieval of cued and context fear in preadolescent (P24 and P33), periadolescent (P37), and adult (P60 and P90) rats. Experiments 3 and 4 examined contextual processing under minimal aversive learning (1 trial) procedures in infant (P19, P21), preadolescent (P24), and adult (P60) rats. Here, we found that male and female rats display a divergent developmental trajectory in the expression of context-mediated freezing, such that context fear expression in males tends to increase toward adulthood, while females displayed an opposite pattern of decreasing context fear expression toward adulthood. Longer (14 d) retention intervals produced an overall heightened context fear expression relative to shorter (1 d) retention intervals an observation consistent with fear incubation. Male, but not Female rats showed increasing generalization of context fear across development. Collectively, these findings provide an initial demonstration that sexual differentiation of contextual fear conditioning emerges prior to puberty and follows a distinct developmental trajectory toward adulthood that strikingly parallels sex differences in the etiology and epidemiology of anxiety and trauma- and stressor-related disorders.
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