P4‐253: Hilar GABAergic interneuron activity controls spatial learning and memory retrieval

Andrews-Zwilling, Yaisa; Gillespie, Anna K.; Kravitz, Alexxai V.; Nelson, Alexandra; Devidze, Nino; Lo, Iris; Yoon, Seo Yeon; Bien-Ly, Nga; Ring, Karen; Zwilling, Daniel; Potter, Gregory B.; Rubenstein, J L; Kreitzer, Anatol C.; Huang, Yadong

doi:10.1016/j.jalz.2013.08.035

Cited by 4 publications

(5 citation statements)

References 38 publications

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“…For example, increased granule cell excitability is observed in hippocampal slices following perforant path stimulation when hilar interneurons are ablated (Ratzliff et al, ). More recently, elevated granule cell firing rates together with increased numbers of cFos‐positive neurons in the DG were observed when hilar GABAergic interneurons were silenced using in vivo optogenetic techniques (Andrews‐Zwilling et al, ). Thus, increasing numbers of activated granule cells following hilar interneuron silencing would diminish the sparse encoding in DG required for optimal pattern separation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, increasing numbers of activated granule cells following hilar interneuron silencing would diminish the sparse encoding in DG required for optimal pattern separation. Consistent with a loss of such function, optogenetic inhibition of hilar interneurons is sufficient to impair spatial learning and memory in mice (Andrews-Zwilling et al, 2012). Although the dentate hilus contains a functionally heterogeneous population of GABAergic interneurons, SOM-expressing hilar interneurons are uniquely positioned to maintain sparse encoding within the granule cell population via feedback inhibition onto granule cell dendrites in the perforant path termination zone (i.e., hilar perforant pathassociated cell [HIPP cell]; Freund and Buzsaki, 1996;Houser, 2007;Myers and Scharfman, 2009).…”

Section: Potential Impact Of Gad67-and Som-immunoreactive Hilar Intermentioning

confidence: 99%

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Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Spiegel

Koh

Vogt

et al. 2013

J of Comparative Neurology

117

116

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Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment.

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Section: Discussionmentioning

confidence: 99%

Section: Potential Impact Of Gad67-and Som-immunoreactive Hilar Intermentioning

confidence: 99%

Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Spiegel

Koh

Vogt

et al. 2013

J of Comparative Neurology

117

116

View full text Add to dashboard Cite

show abstract

“…A plethora of studies using optogenetics have begun to causally interrogate neural circuits in cognition and emotion (Tye and Deisseroth, 2012). Optogenetics permit controlling the activity of cell bodies such as DGCs (Kheirbek et al, 2013) or specific hippocampal sub-region afferents systems (Felix-Ortiz et al, 2013;Lovett-Barron et al, 2014) or specific cell populations such as hilar GABA interneurons (Andrews-Zwilling et al, 2012). Combining optogenetics with optical imaging technologies that enable in vivo imaging of cellular assemblies in awake behaving animals (Chen et al, 2013;Ziv et al, 2013;Gunaydin et al, 2014;Chen et al, 2015b;Jennings et al, 2015;Resendez and Stuber, 2015), will permit assessment of the interplay of different cell-types in DG-CA3 microcircuits and cortical neurons in the context of encoding and re-organization of traumatic memories with passage of time.…”

Section: Re-engineering Intrinsic and Extrinsic Connectivity Of The Dmentioning

confidence: 99%

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

Besnard

Sahay

2015

Neuropsychopharmacol

192

159

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The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)-CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal-cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD.

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“…The spatial impairment in the cKO mice could also be due to more direct effects of aberrant cholinergic signaling on encoding, retrieval and task performance. Prior studies have shown that hilar interneurons play a critical role in water maze performance, which argues that impaired cholinergic modulation of interneurons could mediate the observed spatial deficit in α7 cKO mice (Andrews-Zwilling et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Loss of α7 nicotinic acetylcholine receptors in GABAergic interneurons causes sex-dependent impairments in postnatal neurogenesis and cognitive and social behavior

Otto²,

Ac³

et al. 2020

Preprint

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Neural stem cells within the subgranular zone of the dentate gyrus (DG) generate new neurons that form the granule cell layer during embryonic development and continue to generate new neurons throughout life. The maturation process of newly generated granule cells is modulated by nicotinic acetylcholine receptors (nAChRs), which have been shown to play a role in cell survival, signal modulation, dendritic integration, and memory formation. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, particularly the α7 subunit, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined the effects of conditional deletion of α7 nAChRs in GABAergic interneurons on measures of postnatal neurogenesis and behavioral outcomes. Loss of α7 nAChRs resulted in a decrease of postnatal granule cells, as indicated by reduced GFAP+ cells in the DG, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition, object investigation, and spatial learning. Overall, these findings suggest α7 nAChRs expressed in GABAergic interneurons play an important role in regulating postnatal neurogenesis and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

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P4‐253: Hilar GABAergic interneuron activity controls spatial learning and memory retrieval

Cited by 4 publications

References 38 publications

Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

Loss of α7 nicotinic acetylcholine receptors in GABAergic interneurons causes sex-dependent impairments in postnatal neurogenesis and cognitive and social behavior

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