Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1

Department of Neurology, Laboratory of Neuro Imaging, School of Medicine, University of California, Los Angeles, CA 90095-7334, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2009; 106(28):11794-9. DOI: 10.1073/pnas.0812608106
Source: PubMed


Functional heterogeneity has been investigated for decades in the hippocampal region of the mammalian cerebral cortex, and evidence for vaguely defined "dorsal" and "ventral" regions is emerging. Direct evidence that hippocampal field CA1 displays clear regional, laminar, and pyramidal neuron differentiation is presented here, based on a systematic high-resolution analysis of a publicly accessible, genome-wide expression digital library (Allen Brain Atlas) [Lein et al. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168-176]. First, genetic markers reveal distinct spatial expression domains and subdomains along the longitudinal (dorsal/septal/posterior to ventral/temporal/anterior) axis of field CA1. Second, genetic markers divide field CA1 pyramidal neurons into multiple subtypes with characteristic laminar distributions. And third, subcortical brain regions receiving axonal projections from molecularly distinct spatial domains of field CA1 display distinct global gene expression patterns, suggesting that field CA1 spatial domains may be genetically wired independently to form distinct functional networks related to cognition and emotion. Insights emerging from this genomic-anatomic approach provide a starting point for a detailed analysis of differential hippocampal structure-function organization.

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    • "These domains also differ in gene expression, and in anatomical connections with the rest of the brain, while having relatively similar neural circuitry, and a similar composition of the CA subfields 1–3, dentate gyrus, and subiculum [Moser and Moser, 1998; Fanselow and Dong, 2010; Strange et al., 2014]. In rodent, where the ventral–dorsal axis is equivalent to the human anterior–posterior axis, gene expression patterns define at least three domains: ventral, mid, and dorsal [Dong et al., 2009]. The ventral HPC is involved in motivational behavior, emotional memory, and regulation of neuroendocrine and autonomic activity, via connectivity with the amygdala, medial prefrontal cortex (mPFC), and periventricular hypothalamus, among other areas. "
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    ABSTRACT: The hippocampus (HPC) is functionally heterogeneous along the longitudinal anterior-posterior axis. In rodent models, gene expression maps define at least three discrete longitudinal subregions, which also differ in function, and in anatomical connectivity with the rest of the brain. In humans, equivalent HPC subregions are less well defined, resulting in a lack of consensus in neuroimaging approaches that limits translational study. This study determined whether a data-driven analysis, namely independent component analysis (ICA), could reproducibly define human HPC subregions, and map their respective intrinsic functional connectivity (iFC) with the rest of the brain. Specifically, we performed ICA of resting-state fMRI activity spatially restricted within the HPC, to determine the configuration and reproducibility of functional HPC components. Using dual regression, we then performed multivariate analysis of iFC between resulting HPC components and the whole brain, including detailed connectivity with the hypothalamus, a functionally important connection not yet characterized in human. We found hippocampal ICA resulted in highly reproducible longitudinally discrete components, with greater functional heterogeneity in the anterior HPC, consistent with animal models. Anterior hippocampal components shared iFC with the amygdala, nucleus accumbens, medial prefrontal cortex, posterior cingulate cortex, midline thalamus, and periventricular hypothalamus, whereas posterior hippocampal components shared iFC with the anterior cingulate cortex, retrosplenial cortex, and mammillary bodies. We show that spatially masked hippocampal ICA with dual regression reproducibly identifies functional subregions in the human HPC, and maps their respective brain intrinsic connectivity. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 11/2015; DOI:10.1002/hbm.23042 · 5.97 Impact Factor
    • "An intermediate zone linking the two extremes has also been defined (Dong et al. 2009; Fanselow & Dong, 2010). These subfields of the hippocampus show distinct anatomical connections (Swanson & Cowan, 1977; Witter et al. 1989; Risold & Swanson, 1996; Dolorfo & Amaral, 1998; Prasad & Chudasama, 2013) and gene expression patterns (Lein et al. 2007; Dong et al. 2009). Hippocampal pyramidal neurons have spatially selective firing fields (O'Keefe & Dostrovsky, 1971) and their field size increases almost linearly along the D–V axis (Jung et al. 1994; Maurer et al. 2005; Kjelstrup et al. 2008; Royer et al. 2010). "
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    ABSTRACT: In rodent hippocampi, the connections, gene expression, and functions differ along the dorso-ventral (D-V) axis. CA1 pyramidal cells show increasing excitability along the D-V axis, but the underlying mechanism is not known. In this study we investigated how the M-current (IM), caused by Kv7/M (KCNQ) potassium channels, and known to often control neuronal excitability, contributes to D-V differences in intrinsic properties of CA1 pyramidal cells. Using whole-cell patch clamp recordings and the selective Kv7/M blocker XE991 in hippocampal slices from 3–4 week old rats, we found that: (1) IM had a stronger impact on subthreshold electrical properties in dorsal than in ventral CA1 pyramidal cells, including input resistance, temporal summation, and M-resonance. (2) IM activated at more negative potentials (left-shifted) and had larger peak amplitude in dorsal than in ventral CA1. (3) The initial spike threshold (during ramp depolarizations) was elevated, and the medium after-hyperpolarization (mAHP) and spike frequency adaptation were increased, i.e. excitability was lower, in dorsal than in ventral CA1. These differences were abolished or reduced by application of XE991, indicating that they were caused by IM. Thus, it seems that IM has stronger effects in dorsal than in ventral rat CA1 pyramidal cells, because of a larger maximal M-conductance and left-shifted activation curve in the dorsal cells. These mechanisms may contribute to D-V differences in rate and phase coding of position by CA1 place cells, and may also enhance epileptiform activity in ventral CA1.This article is protected by copyright. All rights reserved
    The Journal of Physiology 12/2014; 593(7). DOI:10.1113/jphysiol.2014.280826 · 5.04 Impact Factor
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    • "The deleterious effects of stress and cortisol on the hippocampus are thought to lead to changes in synaptic plasticity, structural alterations and functional impairments in CA1 neurons (McEwen et al., 1968; de Kloet, 2012). With regard to the organization of CA1 networks, recent animal data suggest a differential organization of CA1 networks into functional compartments, such as the dorsal hippocampus performing cognitive functions and the ventral hippocampus subserving the processing of stress, emotion, and affect (Moser and Moser, 1998; Dong et al., 2009; Fanselow and Dong, 2010). "
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    ABSTRACT: The transient global amnesia (TGA) is a rare amnesic syndrome that is characterized by an acute onset episode of an anterograde and retrograde amnesia. Its origin is still debated, but there is evidence for psychological factors involved in TGA. In neuroimaging, selective lesions in the CA1 fields of the hippocampus can be detected, a region that is particularly involved in the processing of memory, stress and emotion. The aim of this study was to assess the role of psychological stress in TGA by studying the prevalence of stress related precipitating events and individual stress-related personality profiles as well as coping strategies in patients. The hypothesis of a functional differentiation of the hippocampus in mnemonic and stress-related compartments was also evaluated. From all 113 patients, 18 % (n= 24) patients experienced emotional and psychological stress episodes directly before the TGA. In a cohort of 21 acute patients, TGA patients tend to cope with stress less efficiently and less constructively than controls. Patients who experienced a stress related precipitant event exhibited a higher level of anxiety in comparison to non-stress patients and controls. However, there was no difference between the general experience of stress and the number of stress inducing life events. The majority of patients (73%) did show typical MRI lesions in the CA1 region of the hippocampal cornu ammonis. There was no clear association between stressful events, distribution of hippocampal CA1 lesions and behavioral patterns during the TGA. Disadvantageous coping strategies and an elevated anxiety level may increase the susceptibility to psychological stress which may facilitate the pathophysiological cascade in TGA. The findings suggest a role of emotional stress factors in the manifestation of TGA in a subgroup of patients. Stress may be one trigger involved in the emergence of transient lesions in the hippocampal CA1 region, which are thought to be the structural and fun
    Frontiers in Behavioral Neuroscience 08/2014; 8:287. DOI:10.3389/fnbeh.2014.00287 · 3.27 Impact Factor
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