Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice

Kobayashi, Yuki; Sano, Yoshitake; Vannoni, Elisabetta; Goto, Hiromichi; Suzuki, Hitomi; Oba, Atsuko; Kawasaki, Hiroaki; Kanba, Shigenobu; Lipp, Hans‐Peter; Murphy, Niall P.; Wolfer, David P; Itohara, Shigeyoshi

doi:10.3389/fnbeh.2013.00017

Cited by 155 publications

(149 citation statements)

References 52 publications

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“…For conditional deletion, we used camk2a-cre transgenic mice that express cre specifically in forebrain differentiated neurons 16 . By using RNZ reporter mice that express LacZ in nuclei through cre-mediated recombination 17,18 , we confirmed specific recombination by the camk2a-cre transgene in the forebrain region, especially in the cortex and hippocampus (Fig. 1d) 19 .…”

Section: Resultsmentioning

confidence: 55%

“…The camk2a-cre transgenic mice harbouring a transgene containing cre recombinase under the camk2a promoter 16 were obtained from the Jackson Laboratory (Bar Harbor, ME). CAG-cre transgenic mice 43 and RNZ (ROSA26-loxP-STOP-loxP-nlsLacZ) mice 18 were generously provided by Dr Miyazaki (Osaka University) and Dr Itohara (RIKEN BSI), respectively. All mice were maintained on a B6 background.…”

Section: Methodsmentioning

confidence: 99%

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NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

et al. 2014

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Nuclear transcription factor-Y (NF-Y), a key regulator of cell-cycle progression, often loses its activity during differentiation into nonproliferative cells. In contrast, NF-Y is still active in mature, differentiated neurons, although its neuronal significance remains obscure. Here we show that conditional deletion of the subunit NF-YA in postmitotic mouse neurons induces progressive neurodegeneration with distinctive ubiquitin/p62 pathology; these proteins are not incorporated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic ER disorganization, that is, an aberrant increase in ribosome-free ER in the perinuclear region, without inducing ER stress response. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including Grp94 potentially involved in ER disorganization. We propose that NF-Y is involved in a unique regulation mechanism of ER organization in mature neurons and its disruption causes previously undescribed novel neuropathology accompanying abnormal ubiquitin/p62 accumulation.

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Section: Resultsmentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

et al. 2014

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“…IPN neurons project to the raphe nucleus and dorsal tegmentum (Hsu et al, 2013), which provide neurological input to the ventral tegmental area (VTA) (Geisler and Zahm, 2005). Thus far, the MHb and IPN have been linked to anxiety, impulsivity, nicotine withdrawal, and primary reinforcement (Hsu et al, 2014;Kobayashi et al, 2013;Zhao-Shea et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

Harrington

Viñals

Herrera-Solís

et al. 2015

Neuropsychopharmacol

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Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA.

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“…A recent study showed that selectively ablating the MHb neurons led to deficits in spatial memory [6]. Meanwhile, ablation of specific MHb projection neurons amplified the fear responses and learning behavior [15].…”

Section: Introductionmentioning

confidence: 99%

“…The Hb has many functions, but some of these remain to be investigated [1,2]. A few studies have reported that the MHb plays a critical role in stress [3,4], depression [5], memory [6,7], and nicotine withdrawal [8].…”

Section: Introductionmentioning

confidence: 99%

ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory

et al. 2018

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The Medial Habenular (MHb) and the Lateral Habenular nuclei are 2 main parts of the habenular complex (Hb). Recent studies showed that MHb plays an important role in memory, and in the expression of ErbB4. However, the expression of MHb ErbB4 receptor and its role in fear memory is not well understood. In this study, western blotting and quantitative real-time polymerase chain reaction were used to assess the protein and mRNA levels of ErbB4 in the process of contextual fear conditioning. A pharmacological approach was used to block and stimulate the ErbB4 receptor. Contextual fear conditioning tests induced a significant increase on the expression of ErbB4 at various times in the Hb and the MHb. Moreover, the blockade and stimulation of MHb ErbB4 receptors did not affect the fear formation but impaired and improved the contextual-dependent fear expression. Furthermore, in vitro electrophysiological recordings showed that the blockade of the MHb ErbB4 receptor reduced the presynaptic gamma-amino butyric acid release. ErbB4 is a susceptible gene for schizophrenia and the above findings may provide new insights into the mechanisms of fear-related responses.

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Genetic dissection of medial habenula–interpeduncular nucleus pathway function in mice

Cited by 155 publications

References 52 publications

NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

ErbB4 Receptors in the Medial Habenula Regulate Contextual Fear Memory

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