Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats

Abstract

The locus coeruleus (LC) projects throughout the brain and spinal cord and is the major source of central noradrenaline. It remains unclear whether the LC acts functionally as a single global effector or as discrete modules. Specifically, while spinal-projections from LC neurons can exert analgesic actions, it is not known whether they can act independently of ascending LC projections. Using viral vectors taken up at axon terminals, we expressed chemogenetic actuators selectively in LC neurons with spinal (LC:SC) or prefrontal cortex (LC:PFC) projections. Activation of the LC:SC module produced robust, lateralised anti-nociception while activation of LC:PFC produced aversion. In a neuropathic pain model, LC:SC activation reduced hind-limb sensitisation and induced conditioned place preference. By contrast, activation of LC:PFC exacerbated spontaneous pain, produced aversion and increased anxiety-like behaviour. This independent, contrasting modulation of pain-related behaviours mediated by distinct noradrenergic neuronal populations provides evidence for a modular functional organisation of the LC.

Prefrontal circuits signaling active avoidance retrieval and extinction

“…Responses of PL and IL neurons in fear conditioning are regulated by noradrenergic and dopaminergic inputs (Mueller et al 2010, 2008; Pendyam et al 2013). Photoactivation of projections from ventral tegmental area to PL evokes anxiety-like behavior and place aversion (Gunaydin et al 2014), and similar effects were observed with chemoactivation of projections from locus coeruleus to PFC (Hirschberg et al 2017). Inputs from ventral hippocampus to PL and IL have also been implicated in retrieval and extinction of both fear conditioning (Rosas-Vidal et al 2014; Sotres-Bayon et al 2012) and active avoidance (Rosas-Vidal et al 2018).…”

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

“…This particularly important in light of the increased in c‐FOS immunoreactivity observed in the lPBN of DVC::GFAP hM3Dq mice after CNO treatment, which may indicate the activation of a NTS‐lPBN pathway previously reported to reduce food intake through aversion/negative salience (Roman et al, ). To do this, we used a CPA assay utilizing a protocol previously used by our group to indicate aversive responses/negative salience in response to chemogenetic activation of prefrontal cortex‐projecting locus coeruleus neurons (LC PFC ) in rats (Hirschberg, Li, Randall, Kremer, & Pickering, ). We found that after one conditioning session per agent CNO treatment in DVC::GFAP hM3Dq or DVC::GFAP mCherry mice did not induce CPA.…”

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

“…In neuropathy, a disrupted balance of activity in descending monoaminergic systems will also impact the expression of DNIC. Descending noradrenergic pathways remain intact after nerve injury but are hypoactive (Hirschberg et al., ; Hughes, Hickey, Hulse, Lumb, & Pickering, ; Patel, Qu, Xie, Porreca, & Dickenson, ), and DNIC are restored following spinal delivery of a noradrenaline reuptake inhibitor (Bannister et al., ). Chronic pain states can also be associated with increased descending facilitation, largely mediated via spinal 5‐HT 2A and 5‐HT 3 receptors (Patel & Dickenson, ; Suzuki, Rahman, Hunt, & Dickenson, ), and enhanced excitatory drive can mask inhibitory signalling (Bannister et al., ; Nation et al., ; Okada‐Ogawa, Porreca, & Meng, ; Phelps, Navratilova, Dickenson, Porreca, & Bannister, ).…”

“…Prefrontal pyramidal neuronal excitability is suppressed in chronic inflammatory states, and much of this depressed activity derives from feedforward inhibition from GABAergic interneurones targeted by glutamatergic basolateral amygdala projections (Ji & Neugebauer, 2014;Ji et al, 2010). In addition, following nerve injury plasticity in cholinergic modulation can promote functional deactivation (Radzicki, Pollema-Mays, Sanz-Clemente, & Martina, 2017), and increased noradrenergic modulation drives aversive and anxiogenic behaviours (Hirschberg, Li, Randall, Kremer, & Pickering, 2017). Notably, both sensory and affective dimensions of pain can be ameliorated by augmenting this cortical activity as silencing GABAergic interneurones (Zhang et al, 2015), or optogenetic activation of pyramidal neurones (Lee et al, 2015), produces conditioned place preference in neuropathic animals in addition to reversing mechanical and thermal hypersensitivity.…”