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Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

ABSTRACT: Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.

SUBMITTER: Weitz AJ

PROVIDER: S-EPMC4409430 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

Weitz Andrew J AJ Fang Zhongnan Z Lee Hyun Joo HJ Fisher Robert S RS Smith Wesley C WC Choy ManKin M Liu Jia J Lin Peter P Rosenberg Matthew M Lee Jin Hyung JH

NeuroImage 20141022

Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at h ...[more]

PMID: 25462689

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Project description:A fundamental, evolutionarily conserved biological mechanism required for long-term memory formation is rapid induction of gene transcription upon learning in relevant brain areas. For episodic types of memories, two regions undergoing this transcription are the dorsal hippocampus (dHC) and prelimbic (PL) cortex. Whether and to what extent these regions regulate similar or distinct transcriptomic profiles upon learning remain to be understood. Here, we used RNA sequencing in the dHC and PL cortex of male rats to profile their transcriptomes in untrained conditions (baseline) and at 1 h and 6 d after inhibitory avoidance learning. We found that, of 33,713 transcripts, >14,000 were significantly expressed at baseline in both regions and ∼3000 were selectively enriched in each region. Gene Ontology biological pathway analyses indicated that commonly expressed pathways included synapse organization, regulation of membrane potential, and vesicle localization. The enriched pathways in the dHC were gliogenesis, axon development, and lipid modification, while in the PL cortex included vesicle localization and synaptic vesicle cycle. At 1 h after learning, 135 transcripts changed significantly in the dHC and 478 in the PL cortex; of these, only 34 were shared. Biological pathways most significantly regulated by learning in the dHC were protein dephosphorylation, glycogen and glucan metabolism, while in the PL cortex were axon development and axonogenesis. The transcriptome profiles returned to baseline by 6 d after training. Thus, a significant portion of dHC and PL cortex transcriptomic profiles is divergent, and their regulation upon learning is largely distinct and transient.SIGNIFICANCE STATEMENT Long-term episodic memory formation requires gene transcription in several brain regions, including the hippocampus and PFC. The comprehensive profiles of the dynamic mRNA changes that occur in these regions following learning are not well understood. Here, we performed RNA sequencing in the dorsal hippocampus and prelimbic cortex, a PFC subregion, at baseline, 1 h, and 6 d after episodic learning in rats. We found that, at baseline, dorsal hippocampus and prelimbic cortex differentially express a significant portion of mRNAs. Moreover, learning produces a transient regulation of region-specific profiles of mRNA, indicating that unique biological programs in different brain regions underlie memory formation.

Project description:The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO-/-) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg-1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO-/- mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO-/- mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.

Dataset Information

Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

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Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

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