α2 GABAA receptor sub-units in the ventral hippocampus and α5 GABAA receptor sub-units in the dorsal hippocampus mediate anxiety and fear memory

McEown, Kristopher; Treit, Dallas

doi:10.1016/j.neuroscience.2013.08.012

Cited by 28 publications

(18 citation statements)

References 49 publications

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“…Furthermore, in the future it would be of interest to assess the comparative behavioral and neurochemical effects of chronic RXFP3 activation in the dorsal hippocampus, as this region also receives a topographic relaxin‐3 innervation and expresses RXFP3 (Ma & Gundlach, ; Ma et al, ; Tanaka et al, ), and different amino acid, monoamine, and peptide transmitters have been implicated in the control of anxiety via actions in this area in several earlier and recent investigations (see e.g., File, Kenny, & Cheeta, ; Funck, Fracalossi, Vidigal, & Beijamini, ; Gunther, Luczak, Gruteser, Abel, & Baumann, ; McEown & Treit, ; Solati, Zarrindast, & Salari, ).…”

Section: Discussionmentioning

confidence: 99%

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

et al. 2019

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Anxiety disorders are highly prevalent in modern society and better treatments are required. Key brain areas and signaling systems underlying anxiety include prefrontal cortex, hippocampus, and amygdala, and monoaminergic and peptidergic systems, respectively. Hindbrain GABAergic projection neurons that express the peptide, relaxin‐3, broadly innervate the forebrain, particularly the septum and hippocampus, and relaxin‐3 acts via a Gi/o‐protein‐coupled receptor known as the relaxin‐family peptide 3 receptor (RXFP3). Thus, relaxin‐3/RXFP3 signaling is implicated in modulation of arousal, motivation, mood, memory, and anxiety. Ventral hippocampus (vHip) is central to affective and cognitive processing and displays a high density of relaxin‐3‐positive nerve fibers and RXFP3 binding sites, but the identity of target neurons and associated effects on behavior are unknown. Therefore, in adult, male rats, we assessed the neurochemical nature of hippocampal RXFP3 mRNA‐expressing neurons and anxiety‐like and social behavior following chronic RXFP3 activation in vHip by viral vector expression of an RXFP3‐selective agonist peptide, R3/I5. RXFP3 mRNA detected by fluorescent in situ hybridization was topographically distributed across the hippocampus in somatostatin‐ and parvalbumin‐mRNA expressing GABA neurons. Chronic RXFP3 activation in vHip increased anxiety‐like behavior in the light–dark box and elevated‐plus maze, but not the large open‐field test, and reduced social interaction with a conspecific stranger. Our data reveal disruptive effects of persistent RXFP3 signaling on hippocampal GABA networks important in anxiety; and identify a potential therapeutic target for anxiety disorders that warrants further investigation in relevant preclinical models.

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Section: Discussionmentioning

confidence: 99%

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

et al. 2019

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“…Such findings were clearly at odds with results from genetic studies showing that sedation and motor impairments exerted by BZs depend to a high degree on positive modulation of α 1 GABA A receptors (Atack, 2010). The predominantly, though not exclusively hippocampus-based α 5 GABA A receptors are thought to contribute to amnesic effects of BZs (Rudolph and Möhler, 2006), but their biological role is also the subject of debate, because a number of results suggest that activation of these receptors may facilitate memory processing (Koh et al, 2013; McEown and Treit, 2013), as well as reduce psychotic symptoms (Gill et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects

et al. 2014

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Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABAA receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently non-selective modulators. We report on SH-I-048A, a newly-synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at α1- and α5-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 hours after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at α1-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the α5 subunit. The current results encourage further innovative approaches aimed at linking in vitro and in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.

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“…While this is an important characteristic, it often overshadows other imperative functions of the hippocampus—especially the mediation of unconditioned emotional responding. Recently, there has been a growing number of studies providing evidence for the dissociation between the dorsal and ventral hippocampus, implicating the ventral hippocampus in the mediation of anxiety (Gray and McNaughton, ; Kjelstrup et al, ; Degroot and Treit, ; Adhikari et al, ; McEown and Treit, ; Marrocco et al, ; Albrecht et al, ; Kheirbek et al, ; McEown and Treit, ). A reduction in anxiety‐related behaviors can be demonstrated when disrupting ventral, but not dorsal, hippocampal function with permanent lesions (Kjelstrup et al, ; Pentkowski et al, ) or reversible neural inactivation using TTX, lidocaine, muscimol, or glutamatergic antagonists (Degroot and Treit, ; Nascimento Hackl and Carobrez, ; McEown and Treit, ; McEown and Treit, ).…”

Section: Introductionmentioning

confidence: 99%

ANI inactivation: Unconditioned anxiolytic effects of anisomycin in the ventral hippocampus

Greenberg

Ward-Flanagan

Dickson³

et al. 2014

Hippocampus

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Although hippocampal function is typically described in terms of memory, recent evidence suggests a differentiation along its dorsal/ventral axis, with dorsal regions serving memory and ventral regions serving emotion. While long-term memory is thought to be dependent on de novo protein synthesis because it is blocked by translational inhibitors such as anisomycin (ANI), online (moment-to-moment) functions of the hippocampus (such as unconditioned emotional responding) should not be sensitive to such manipulations since they are unlikely to involve neuroplasticity. However, ANI has recently been shown to suppress neural activity which suggests (1) that protein synthesis is critical for neural function and (2) that paradigms using ANI are confounded by its inactivating effects. We tested this idea using a neurobehavioral assay which compared the influence of intrahippocampal infusions of ANI at dorsal and ventral sites on unconditioned emotional behavior of rats. We show that ANI infusions in ventral, but not dorsal, hippocampus produced a suppression of anxiety-related responses in two well-established rodent tests: the elevated plus maze and shock-probe burying tests. These results are similar to those previously observed when ventral hippocampal activity is directly suppressed (e.g., by using sodium channel blockers). The present study offers compelling behavioral evidence for the proposal that ANI adversely affects ongoing neural function and therefore its influence is not simply limited to impairing the consolidation of long-term memories

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α2 GABAA receptor sub-units in the ventral hippocampus and α5 GABAA receptor sub-units in the dorsal hippocampus mediate anxiety and fear memory

Cited by 28 publications

References 49 publications

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects

ANI inactivation: Unconditioned anxiolytic effects of anisomycin in the ventral hippocampus

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