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: 9.81). 07/2009; 106(28):11794-9. DOI: 10.1073/pnas.0812608106
Source: PubMed

ABSTRACT 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.

    • "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 · 4.54 Impact Factor
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    • "The emerging picture of division of labor between hippocampal region (and subicular) differentiations (Risold and Swanson, 1996; Swanson, 2004; Pentkowski et al., 2006; Dong et al., 2009; Bast et al., 2009; Royer et al., 2010; Fanselow and Dong, 2010) is enhanced by a deepening knowledge of hippocampal region functional dynamics (Lubenov and Siapas, 2009) and increasing awareness of the existence of a partially overlapping yet highly conserved topography in the connections of the HPF, as is indicated by the present data for HPF projections to the LHAjd and LHAjp, and as is also characteristic of most (if not all) other HPF intrinsic and extrinsic connections studied to date (for examples, see Swanson and Cowan, 1975; Swanson and Cowan, 1977; Swanson et al., 1978; Swanson, 1978; Swanson et al., 1981; Swanson and Kohler, 1986; Swanson et al., 1987; van Groen and Wyss, 1990a; van Groen and Wyss, 1990b; van Groen and Wyss, 1990c; Risold and Swanson, 1996; Kishi et al., 2000; Burwell, 2000; Petrovich et al., 2001; Witter and Amaral, 2004; Kishi et al., 2006; Cenquizca and Swanson, 2006; Cenquizca and Swanson, 2007; Dong et al., 2009; Hahn and Swanson, 2010). The precise functional significance of these topographic relations remains to be determined. "
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    ABSTRACT: Evolutionary conservation of the hypothalamus attests to its critical role in the control of fundamental behaviors. However, our knowledge of hypothalamic connections is incomplete, particularly for the lateral hypothalamic area (LHA). Here we present the results of neuronal pathway-tracing experiments to investigate connections of the LHA juxtaventromedial region, which is parceled into dorsal (LHAjvd) and ventral (LHAjvv) zones. Phaseolus vulgaris leucoagglutinin (PHAL, for outputs) and cholera toxin B subunit (CTB, for inputs) coinjections were targeted stereotaxically to the LHAjvd/v. Results: LHAjvd/v connections overlapped highly but not uniformly. Major joint outputs included: Bed nuc. stria terminalis (BST), interfascicular nuc. (BSTif) and BST anteromedial area, rostral lateral septal (LSr)- and ventromedial hypothalamic (VMH) nuc., and periaqueductal gray. Prominent joint LHAjvd/v input sources included: BSTif, BST principal nuc., LSr, VMH, anterior hypothalamic-, ventral premammillary-, and medial amygdalar nuc., and hippocampal formation (HPF) field CA1. However, LHAjvd HPF retrograde labeling was markedly more abundant than from the LHAjvv; in the LSr this was reversed. Furthermore, robust LHAjvv (but not LHAjvd) targets included posterior- and basomedial amygdalar nuc., whereas the midbrain reticular nuc. received a dense input from the LHAjvd alone. Our analyses indicate the existence of about 500 LHAjvd and LHAjvv connections with about 200 distinct regions of the cerebral cortex, cerebral nuclei, and cerebrospinal trunk. Several highly LHAjvd/v-connected regions have a prominent role in reproductive behavior. These findings contrast with those from our previous pathway-tracing studies of other LHA medial and perifornical tier regions, with different connectional behavioral relations. The emerging picture is of a highly differentiated LHA with extensive and far-reaching connections that point to a role as a central coordinator of behavioral control.
    The Journal of Comparative Neurology 06/2012; 520(9):1831-90. DOI:10.1002/cne.23064 · 3.51 Impact Factor
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    • "entorhinal cortex and the site of adult neurogenesis, project to the large pyramidal cells of layer CA3 in the ' cortical ' hippocampus ; these, in turn, project, through the Shaffer collaterals, to the pyramidal cells of CA1 (Fig. 3). There is a complex non-uniform pattern of gene expression throughout CA1 (Dong et al. 2009). Different parts of the hippocampus may be involved in many neural disorders, including MDD (Small et al. 2011). "
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    ABSTRACT: BACKGROUND: Cortisol plays a multifaceted role in major depression disorder (MDD). Diurnal rhythms are disturbed, there is increased resistance to the feedback action of glucocorticoids, excess cortisol may induce MDD, basal levels may be higher and the post-awakening cortisol surge accentuated in those at risk for MDD. Does this suggest new avenues for studying MDD or its clinical management?Method The relevant literature was reviewed. RESULTS: Cortisol contributes to genetic variants for the risk for MDD and the way that environmental events amplify risk. The corticoids' influence begins prenatally, but continues into adulthood. The impact of cortisol at each phase depends not only on its interaction with other factors, such as psychological traits and genetic variants, but also on events that have, or have not, occurred previously. CONCLUSIONS: This review suggests that the time is now right for serious consideration of the role of cortisol in a clinical context. Estimates of cortisol levels and the shape of the diurnal rhythm might well guide the understanding of subtypes of MDD and yield additional indicators for optimal treatment. Patients with disturbed cortisol rhythms might benefit from restitution of those rhythms; they may be distinct from those with more generally elevated levels, who might benefit from cortisol blockade. Higher levels of cortisol are a risk for subsequent depression. Should manipulation of cortisol or its receptors be considered as a preventive measure for some of those at very high risk of future MDD, or to reduce other cortisol-related consequences such as long-term cognitive decline?
    Psychological Medicine 05/2012; 43(3):1-21. DOI:10.1017/S0033291712000955 · 5.43 Impact Factor
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