The Distribution of Toxoplasma gondii Cysts in the Brain of a Mouse with Latent Toxoplasmosis: Implications for the Behavioral Manipulation Hypothesis

reportedly manipulates rodent behavior to enhance the likelihood of transmission to its definitive cat host. The proximate mechanisms underlying this adaptive manipulation remain largely unclear, though a growing body of evidence suggests that the parasite-entrained dysregulation of dopamine metabolism plays a central role. Paradoxically, the distribution of the parasite in the brain has received only scant attention. at six months of age and examined 18 weeks later. The cysts were distributed throughout the brain and selective tropism of the parasite toward a particular functional system was not observed. Importantly, the cysts were not preferentially associated with the dopaminergic system and absent from the hypothalamic defensive system. The striking interindividual differences in the total parasite load and cyst distribution indicate a probabilistic nature of brain infestation. Still, some brain regions were consistently more infected than others. These included the olfactory bulb, the entorhinal, somatosensory, motor and orbital, frontal association and visual cortices, and, importantly, the hippocampus and the amygdala. By contrast, a consistently low incidence of tissue cysts was recorded in the cerebellum, the pontine nuclei, the caudate putamen and virtually all compact masses of myelinated axons. Numerous perivascular and leptomeningeal infiltrations of inflammatory cells were observed, but they were not associated with intracellular cysts. distribution stems from uneven brain colonization during acute infection and explains numerous behavioral abnormalities observed in the chronically infected rodents. Thus, the parasite can effectively change behavioral phenotype of infected hosts despite the absence of well targeted tropism

Goal-oriented searching mediated by ventral hippocampus early in trial-and-error learning

Most behavioral learning in biology is trial and error, but how these learning processes are influenced by individual brain systems is poorly understood. Here we show that ventral-to-dorsal hippocampal subdivisions have specific and sequential functions in trial-and-error maze navigation, with ventral hippocampus (vH) mediating early task-specific goal-oriented searching. Although performance and strategy deployment progressed continuously at the population level, individual mice showed discrete learning phases, each characterized by particular search habits. Transitions in learning phases reflected feedforward inhibitory connectivity (FFI) growth occurring sequentially in ventral, then intermediate, then dorsal hippocampal subdivisions. FFI growth at vH occurred abruptly upon behavioral learning of goal-task relationships. vH lesions or the absence of vH FFI growth delayed early learning and disrupted performance consistency. Intermediate hippocampus lesions impaired intermediate place learning, whereas dorsal hippocampus lesions specifically disrupted late spatial learning. Trial-and-error navigational learning processes in naive mice thus involve a stereotype sequence of increasingly precise subtasks learned through distinct hippocampal subdivisions. Because of its unique connectivity, vH may relate specific goals to internal states in learning under healthy and pathological conditions

Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus

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