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      Optogenetic Activation of CA1 Pyramidal Neurons at the Dorsal and Ventral Hippocampus Evokes Distinct Brain-Wide Responses Revealed by Mouse fMRI

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          The dorsal and ventral hippocampal regions (dHP and vHP) are proposed to have distinct functions. Electrophysiological studies have revealed intra-hippocampal variances along the dorsoventral axis. Nevertheless, the extra-hippocampal influences of dHP and vHP activities remain unclear. In this study, we compared the spatial distribution of brain-wide responses upon dHP or vHP activation and further estimate connection strengths between the dHP and the vHP with corresponding extra-hippocampal areas. To achieve this, we first investigated responses of local field potential (LFP) and multi unit activities (MUA) upon light stimulation in the hippocampus of an anesthetized transgenic mouse, whose CA1 pyramidal neurons expressed a step-function opsin variant of channelrhodopsin-2 (ChR2). Optogenetic stimulation increased hippocampal LFP power at theta, gamma, and ultra-fast frequency bands, and augmented MUA, indicating light-induced activation of CA1 pyramidal neurons. Brain-wide responses examined using fMRI revealed that optogenetic activation at the dHP or vHP caused blood oxygenation level-dependent (BOLD) fMRI signals in situ. Although activation at the dHP induced BOLD responses at the vHP, the opposite was not observed. Outside the hippocampal formation, activation at the dHP, but not the vHP, evoked BOLD responses at the retrosplenial cortex (RSP), which is in line with anatomical evidence. In contrast, BOLD responses at the lateral septum (LS) were induced only upon vHP activation, even though both dHP and vHP send axonal fibers to the LS. Our findings suggest that the primary targets of dHP and vHP activation are distinct, which concurs with attributed functions of the dHP and RSP in spatial memory, as well as of the vHP and LS in emotional responses.

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          Most cited references 41

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          Unsupervised spike detection and sorting with wavelets and superparamagnetic clustering.

          This study introduces a new method for detecting and sorting spikes from multiunit recordings. The method combines the wavelet transform, which localizes distinctive spike features, with superparamagnetic clustering, which allows automatic classification of the data without assumptions such as low variance or gaussian distributions. Moreover, an improved method for setting amplitude thresholds for spike detection is proposed. We describe several criteria for implementation that render the algorithm unsupervised and fast. The algorithm is compared to other conventional methods using several simulated data sets whose characteristics closely resemble those of in vivo recordings. For these data sets, we found that the proposed algorithm outperformed conventional methods.
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            Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons

            Ventral tegmental area (VTA) dopamine (DA) neurons in the brain’s reward circuit play a crucial role in mediating stress responses 1–4 including determining susceptibility vs. resilience to social stress-induced behavioural abnormalities 5 . VTA DA neurons exhibit two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing 6–8 . Phasic firing of the neurons, which is well known to encode reward signals 6,7,9 , is upregulated by repeated social defeat stress, a highly validated mouse model of depression 5,8,10–13 . Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no change in firing rate apparent in resilient individuals 5,8 . However, direct evidence linking—in real-time—DA neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here, we took advantage of the temporal precision and cell type- and projection pathway-specificity of optogenetics to demonstrate that enhanced phasic firing of these neurons mediates susceptibility to social defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing, in VTA DA neurons of mice undergoing a subthreshold social defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social defeat stress. Furthermore, we show differences in projection pathway-specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, while inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing pattern- and neural circuit-specific mechanisms of depression.
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              Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1.

              Most functional brain imaging studies use task-induced hemodynamic responses to infer underlying changes in neuronal activity. In addition to increases in cerebral blood flow and blood oxygenation level-dependent (BOLD) signals, sustained negative responses are pervasive in functional imaging. The origin of negative responses and their relationship to neural activity remain poorly understood. Through simultaneous functional magnetic resonance imaging and electrophysiological recording, we demonstrate a negative BOLD response (NBR) beyond the stimulated regions of visual cortex, associated with local decreases in neuronal activity below spontaneous activity, detected 7.15 +/- 3.14 mm away from the closest positively responding region in V1. Trial-by-trial amplitude fluctuations revealed tight coupling between the NBR and neuronal activity decreases. The NBR was associated with comparable decreases in local field potentials and multiunit activity. Our findings indicate that a significant component of the NBR originates in neuronal activity decreases.

                Author and article information

                Role: Academic Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                20 March 2015
                : 10
                : 3
                [1 ]Department of Neuropsychiatry, School of Medicine, Keio University, Shinjuku, Tokyo, Japan
                [2 ]Department of Physiology, School of Medicine, Keio University, Shinjuku, Tokyo, Japan
                [3 ]Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan
                [4 ]Department of Psychiatry, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
                Indiana University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NT KFT. Performed the experiments: NT KY YK MX. Analyzed the data: NT YK YS. Contributed reagents/materials/analysis tools: KFT KH MM HO. Wrote the paper: NT KFT.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 5, Tables: 1, Pages: 17
                This work was supported by KAKENHI Grants (25430011 and 25115726 to N.T., 24111551 to K.F.T.) and "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)" to H.O. from Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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