Serotonin receptor 1A knockout (Htr1a(KO)) mice show increased anxiety-related behavior in tests measuring innate avoidance. Here we demonstrate that Htr1a(KO) mice show enhanced fear conditioning to ambiguous conditioned stimuli, a hallmark of human anxiety. To examine the involvement of specific forebrain circuits in this phenotype, we developed a pharmacogenetic technique for the rapid tissue- and cell type-specific silencing of neural activity in vivo. Inhibition of neurons in the central nucleus of the amygdala suppressed conditioned responses to both ambiguous and nonambiguous cues. In contrast, inhibition of hippocampal dentate gyrus granule cells selectively suppressed conditioned responses to ambiguous cues and reversed the knockout phenotype. These data demonstrate that Htr1a(KO) mice have a bias in the processing of threatening cues that is moderated by hippocampal mossy-fiber circuits, and suggest that the hippocampus is important in the response to ambiguous aversive stimuli.

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KO)] display increased innate and conditioned anxiety-related behavior. Expression of the receptor in the mouse forebrain during development is sufficient to restore normal anxiety-related behavior to knock-out mice, demonstrating a role for serotonin in the developmental programming of anxiety circuits. However, the precise developmental period as well as the signaling pathways and neural substrates involved in this phenomenon are unknown. Here, we show that pharmacological blockade of the receptor from postnatal day 13 (P13)-P34 is sufficient to reproduce the knock-out phenotype in adulthood, thus defining a role for serotonin in the maturation and refinement of anxiety circuits during a limited postnatal period. Furthermore, we identify increases in the phosphorylation of ␣-Ca 2ϩ /calmodulin-dependent protein kinase II (␣CaMKII) at threonine 286 in the hippocampus of young Htr1a KO mice under anxiety-provoking conditions. Increases in ␣CaMKII phosphorylation were most pronounced in the CA1 region of the hippocampus and were localized to the extrasynaptic compartment, consistent with a tissue-specific effect of the receptor. No changes in ␣CaMKII phosphorylation were found in adult knock-out mice, suggesting a transient role of ␣CaMKII as a downstream target of the receptor. Finally, the anxiety phenotype was abolished when knock-out mice were crossed to mice in which ␣CaMKII phosphorylation was compromised by the heterozygous mutation of threonine 286 into alanine. These findings suggest that modulation of ␣CaMKII function by serotonin during a restricted postnatal period contributes to the developmental programming of anxiety-related behavior.

Mice lacking serotonin receptor 1A (Htr1a) display increased anxiety behavior that depends on the expression of the receptor in the forebrain during the third to fifth postnatal weeks. Within the forebrain, Htr1a is prominently expressed in the soma and dendrites of CA1 pyramidal neurons of the hippocampus and these cells undergo rapid dendritic growth and synapse formation during this period. Consistent with a possible role of Htr1a in synaptic maturation, CA1 pyramidal neurons in the knockout mice show increased ramification of oblique dendrites. These findings suggest that Htr1a may shape hippocampal circuits by directly modulating dendritic growth. Here we show that pharmacological blockade of the receptor during the third to fifth postnatal weeks is sufficient to reproduce the increased branching of oblique dendrites seen in knockout mice. Using dissociated hippocampal cultures we demonstrate that serotonin functions through Htr1a to attenuate the motility of dendritic growth cones, reduce their content of filamentous actin and alter their morphology. These findings suggest that serotonin modulates actin cytoskeletal dynamics in hippocampal neurons during a limited developmental period to restrict dendritic growth and achieve a long-term adjustment of neural connectivity.

Collectively, our findings demonstrate that sensitization to cocaine in early life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans.

The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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