Abstract
Increased anxiety is a predominant withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear. Here, we show that withdrawal-induced anxiety increases activity of neurons in the interpeduncular intermediate (IPI), a subregion of the interpeduncular nucleus (IPN). IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signaling, which modulated glutamatergic input from the medial habenula (MHb). Pharmacological blockade of IPN CRF1 receptors or optogenetic silencing of MHb input reduced IPI activation and alleviated withdrawal-induced anxiety; whereas IPN CRF infusion in mice increased anxiety. We identified a meso-interpeduncular circuit, consisting of ventral tegmental area (VTA) dopaminergic neurons projecting to the IPN, as a potential source of CRF. Knock-down of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal. These data indicate that increased CRF receptor signaling within a VTA-IPN-MHb circuit triggers anxiety during nicotine withdrawal.
Highlights
Increased anxiety is a prominent withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear
We show that corticotropin releasing factor (CRF) inputs from the ventral tegmental area (VTA) and glutamatergic inputs from the medial habenula (MHb) converge onto a subset of interpeduncular nucleus (IPN) neurons to regulate anxiety during nicotine withdrawal via CRF type 1 (CRF1) receptor activation
We show that the IPN is a brain region critical for the anxiogenic effects of nicotine withdrawal
Summary
Increased anxiety is a prominent withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear. IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signalling, which modulated glutamatergic input from the medial habenula (MHb). Knockdown of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal These data indicate that increased CRF receptor signalling within a VTA–IPN–MHb circuit triggers anxiety during nicotine withdrawal. While the vast majority of studies on nicotine dependence in animal models have focused on the traditional mesocorticolimbic ‘reward’ circuitry of the central nervous system (CNS)[5,6,7,8,9], a much more understudied circuit that may be critical for nicotine dependence—the habenulo-interpeduncular pathway10–12—has recently gained attention This circuit consists of the habenula (Hb), a small, epithalamic structure, that can be divided into medial (MHb) and lateral (LHb) sub-regions[13]. We show that CRF inputs from the VTA and glutamatergic inputs from the MHb converge onto a subset of IPN neurons to regulate anxiety during nicotine withdrawal via CRF1 receptor activation
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