Nucleus incertus inactivation impairs spatial learning and memory in rats

Nategh, Mohsen; Nikseresht, Sara; Khodagholi, Fariba; Motamedi, Fereshteh

doi:10.1016/j.physbeh.2014.11.014

Cited by 31 publications

(26 citation statements)

References 46 publications

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“…However, the precise roles of GABA and relaxin-3 in this process remain to be determined. Consistent with a role in the control of hippocampal theta rhythm, inactivation of NI with lidocaine impairs the acquisition and retrieval of spatial reference memory (60). …”

Section: Brainstem Gabaergic Neurons Controlling Theta Rhythmsmentioning

confidence: 88%

Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

Brown

Mckenna

2015

Front. Neurol.

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Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Recent technological advances have illuminated the role of GABAergic neurons in control of cortical arousal and sleep. Sleep-promoting GABAergic neurons in the preoptic hypothalamus are well-known. Less well-appreciated are GABAergic projection neurons in the brainstem, midbrain, hypothalamus, and basal forebrain, which paradoxically promote arousal and fast electroencephalographic (EEG) rhythms. Thus, GABA is not purely a sleep-promoting neurotransmitter. GABAergic projection neurons in the brainstem nucleus incertus and ventral tegmental nucleus of Gudden promote theta (4–8 Hz) rhythms. Ventral tegmental area GABAergic neurons, neighboring midbrain dopamine neurons, project to the frontal cortex and nucleus accumbens. They discharge faster during cortical arousal and regulate reward. Thalamic reticular nucleus GABAergic neurons initiate sleep spindles in non-REM sleep. In addition, however, during wakefulness, they tonically regulate the activity of thalamocortical neurons. Other GABAergic inputs to the thalamus arising in the globus pallidus pars interna, substantia nigra pars reticulata, zona incerta, and basal forebrain regulate motor activity, arousal, attention, and sensory transmission. Several subpopulations of cortically projecting GABAergic neurons in the basal forebrain project to the thalamus and neocortex and preferentially promote cortical gamma-band (30–80 Hz) activity and wakefulness. Unlike sleep-active GABAergic neurons, these ascending GABAergic neurons are fast-firing neurons which disinhibit and synchronize the activity of their forebrain targets, promoting the fast EEG rhythms typical of conscious states. They are prominent targets of GABAergic hypnotic agents. Understanding the properties of ascending GABAergic neurons may lead to novel treatments for diseases involving disorders of cortical activation and wakefulness.

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Section: Brainstem Gabaergic Neurons Controlling Theta Rhythmsmentioning

confidence: 88%

Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

Brown

Mckenna

2015

Front. Neurol.

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“…Our findings substantially expand the earlier findings which provided initial clues that the NI may participate in integrative modulation of locomotion, arousal, and/or hippocampal theta. It was known that stimulating (or even ablating) the NI promotes locomotor activity 16,17 . Moreover, non-cell-type-specific chemogenetic stimulation of the neurons within and near the NI promotes the cortical desynchronization that is often associated with increased arousal 15 .…”

Section: Discussionmentioning

confidence: 99%

“…It remains unknown how these behavioral and physiological processes are coordinately organized. Previous studies have hinted that the nucleus incertus (NI)-a brain region in the pontine brainstem-may be involved in some of these processes [15][16][17][18] , although the underlying cell-type-specific circuit mechanisms have not been elucidated. Located in the midline central gray of the dorsal pons, the NI contains intermingled GABAergic 19,20 and glutamatergic 19,21 neurons, and expresses several markers, including neuromedin B (NMB), relaxin-3 (Rln3), the type 1 corticotropin-releasing factor receptor (CRFR1), the D 2 -type dopamine receptor (D2R), and the orexin/hypocretin receptor 19,[22][23][24][25][26] .…”

mentioning

confidence: 99%

Control of locomotor speed, arousal, and hippocampal theta rhythms by the nucleus incertus

Ren

et al. 2020

Nat Commun

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Navigation requires not only the execution of locomotor programs but also high arousal and real-time retrieval of spatial memory that is often associated with hippocampal theta oscillations. However, the neural circuits for coordinately controlling these important processes remain to be fully dissected. Here we show that the activity of the neuromedin B (NMB) neurons in the nucleus incertus (NI) is tightly correlated with mouse locomotor speed, arousal level, and hippocampal theta power. These processes are reversibly suppressed by optogenetic inhibition and rapidly promoted by optogenetic stimulation of NI NMB neurons. These neurons form reciprocal connections with several subcortical areas associated with arousal, theta oscillation, and premotor processing. Their projections to multiple downstream stations regulate locomotion and hippocampal theta, with the projection to the medial septum being particularly important for promoting arousal. Therefore, NI NMB neurons functionally impact the neural circuit for navigation control according to particular brains states.

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“…More recently, it was reported that lidocaine infusion into the NI impaired long‐term spatial memory of adult rats in a Morris water maze (MWM) (Nategh et al, ) and delayed learning and impaired retention in a passive avoidance learning (PAL) task (Nategh et al, ), which are both hippocampal‐dependent memory tasks. In the latter study, perforant path‐DG short‐term synaptic plasticity was also examined upon NI inactivation, both before a paired‐pulse stimulation, and before or after tetanic stimulation, in freely moving rats; revealing that NI inactivation did not change the perforant path‐DG granule cell synaptic input, but decreased the excitability of DG granule cells, consistent with an effect of normal NI activity to inhibit the inhibitory interneurons in the DG and disinhibit granule cells (Nategh et al, ).…”

Section: Introductionmentioning

confidence: 99%

Relaxin‐3 inputs target hippocampal interneurons and deletion of hilar relaxin‐3 receptors in “floxed‐RXFP3” mice impairs spatial memory

et al. 2017

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Hippocampus is innervated by γ-aminobutyric acid (GABA) "projection" neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at gaining an understanding of the role of RLN3 signaling in hippocampus via its G -protein-coupled receptor, RXFP3, we examined the distribution of RLN3-immunoreactive nerve fibres and RXFP3 mRNA-positive neurons in relation to hippocampal GABA neuron populations. RLN3-positive elements were detected in close-apposition with a substantial population of somatostatin (SST)- and GABA-immunoreactive neurons, and a smaller population of parvalbumin- and calretinin-immunoreactive neurons in different hippocampal areas, consistent with the relative distribution patterns of RXFP3 mRNA and these marker transcripts. In light of the functional importance of the dentate gyrus (DG) hilus in learning and memory, and our anatomical data, we examined the possible influence of RLN3/RXFP3 signaling in this region on spatial memory. Using viral-based Cre/LoxP recombination methods and adult mice with a floxed Rxfp3 gene, we deleted Rxfp3 from DG hilar neurons and assessed spatial memory performance and affective behaviors. Following infusions of an AAV -Cre-IRES-eGFP vector, Cre expression was observed in DG hilar neurons, including SST-positive cells, and in situ hybridization histochemistry for RXFP3 mRNA confirmed receptor depletion relative to levels in floxed-RXFP3 mice infused with an AAV -eGFP (control) vector. RXFP3 depletion within the DG hilus impaired spatial reference memory in an appetitive T-maze task reflected by a reduced percentage of correct choices and increased time to meet criteria, relative to control. In a continuous spontaneous alternation Y-maze task, RXFP3-depleted mice made fewer alternations in the first minute, suggesting impairment of spatial working memory. However, RXFP3-depleted and control mice displayed similar locomotor activity, anxiety-like behavior in light/dark box and elevated-plus maze tests, and learning and long-term memory retention in the Morris water maze. These data indicate endogenous RLN3/RXFP3 signaling can modulate hippocampal-dependent spatial reference and working memory via effects on SST interneurons, and further our knowledge of hippocampal cognitive processing. © 2017 Wiley Periodicals, Inc.

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Nucleus incertus inactivation impairs spatial learning and memory in rats

Cited by 31 publications

References 46 publications

Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

Control of locomotor speed, arousal, and hippocampal theta rhythms by the nucleus incertus

Relaxin‐3 inputs target hippocampal interneurons and deletion of hilar relaxin‐3 receptors in “floxed‐RXFP3” mice impairs spatial memory

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