JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Abstract

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.

mTORC1 senses stresses: Coupling stress to proteostasis

“…). In further support of a causative role of JNK activation in anxiety and depression, in mice Jnk1 deletion promotes hippocampal neurogenesis, alleviating anxiety, and depressive‐like behaviors . Taken together, further efforts are warranted to fully elucidate the roles of mTORC1 and JNK in psychological stress, which is crucial to our better understanding of anxiety and depression, and may further open new therapeutic avenues.…”

Optogenetic Control of Spine-Head JNK Reveals a Role in Dendritic Spine Regression

“…Although ketamine regulation of spines in prefrontal cortex has been dissociated from its behavioral effect in mice (Moda-Sava et al, 2019), the relevance of ketamine or JNK inhibition on spine dynamics in hippocampus has not been studied in the context of depression. It is worth noting however, that like ketamine, Jnk1 deletion or JNK inhibition using the same peptide inhibitor that is encoded in our optogenetic tool, lowers anxietyand depressive-like behaviors in mice (Hollos et al, 2018;Mohammad et al, 2018).…”

“…We were interested to know whether JNK regulated spine retraction in the context of synaptic pathology because JNK1 was recently reported to control depressive and anxiety-like behaviors in mice (Hollos et al, 2018;Mohammad et al, 2018). We therefore used corticosterone, the principal glucocorticoid stress hormone in mice, which stimulates retraction of dendritic spines in specific brain regions (Liston and Gan, 2011).…”

“…It has also been shown that interleukin, ␤-amyloid and restraint-stress-induced activation of JNK impairs hippocampal LTP (Curran et al, 2003;Costello and Herron, 2004;Sherrin et al, 2011). Evidence from animal studies and human genetics studies suggest that dysregulation of the JNK pathway may be linked to psychiatric disorders (Winchester et al, 2012;Kunde et al, 2013;McGuire et al, 2017;Mohammad et al, 2018;Kowalchuk et al, 2019;Openshaw et al, 2019). For example, inhibition or genetic deletion of Jnk1 reduces anxiety and depressive-like behaviors in mice (Mohammad et al, 2018), and MAP2K7 heterozygote mice display brain imaging endophenotypes and behaviors related to schizophrenia (Openshaw et al, 2020).…”

“…Evidence from animal studies and human genetics studies suggest that dysregulation of the JNK pathway may be linked to psychiatric disorders (Winchester et al, 2012;Kunde et al, 2013;McGuire et al, 2017;Mohammad et al, 2018;Kowalchuk et al, 2019;Openshaw et al, 2019). For example, inhibition or genetic deletion of Jnk1 reduces anxiety and depressive-like behaviors in mice (Mohammad et al, 2018), and MAP2K7 heterozygote mice display brain imaging endophenotypes and behaviors related to schizophrenia (Openshaw et al, 2020). Although JNK has been shown to regulate synaptic plasticity in learning and the JNK pathway is genetically associated with disorders of synaptic function; mechanistic study of JNK function in dendritic spines has been limited due to lack of tools that allow spatiotemporal control of the kinase solely in the spine-head.…”