Pain Related Quality of Life in Neurofibromatosis Type 1: A Narrative Review.

PURPOSE OF REVIEW: The purpose of this narrative review is to summarize pain symptomatology and mechanisms in neurofibromatosis type 1 (NF1), discuss the pain related quality of life impacts of NF1, and discuss the literature exploring interventions to improve quality of life. RECENT FINDINGS: Chronic pain in NF1 is described as headache and non-headache pain. The literature describes mechanisms contributing to neuronal hyperexcitability in the setting of reduced neurofibromin as key contributors to pain in NF1. Pain in NF1 negatively impacts quality of life with pain interference, depression, anxiety, and cognitive functioning acting as important mediators. Mitogen-activated protein kinase (MEK) inhibitors are pharmacologic agents that interfere with pain mechanisms. Mind-body interventions improve coping skills to improve quality of life. Chronic pain in NF1 is heterogeneous with negative impacts on quality of life. New developments in pharmacological and non-pharmacological interventions offer promising approaches to pain management and quality of life improvement. Additional research is necessary to validate the use of MEK inhibitors and mind-body interventions in the treatment of NF1.

Activation of Basolateral Amygdala to Nucleus Accumbens Projection Neurons Attenuates Chronic Corticosterone-Induced Behavioral Deficits in Male Mice.

The basolateral amygdala (BLA) is critical for reward behaviors via a projection to the nucleus accumbens (NAc). Specifically, BLA-NAc projections are involved in reinforcement learning, reward-seeking, sustained instrumental responding, and risk behaviors. However, it remains unclear whether chronic stress interacts with BLA-NAc projection neurons to result in maladaptive behaviors. Here we take a chemogenetic, projection-specific approach to clarify how NAc-projecting BLA neurons affect avoidance, reward, and feeding behaviors in male mice. Then, we examine whether chemogenetic activation of NAc-projecting BLA neurons attenuates the maladaptive effects of chronic corticosterone (CORT) administration on these behaviors. CORT mimics the behavioral and neural effects of chronic stress exposure. We found a nuanced role of BLA-NAc neurons in mediating reward behaviors. Surprisingly, activation of BLA-NAc projections rescues CORT-induced deficits in the novelty suppressed feeding, a behavior typically associated with avoidance. Activation of BLA-NAc neurons also increases instrumental reward-seeking without affecting free-feeding in chronic CORT mice. Taken together, these data suggest that NAc-projecting BLA neurons are involved in chronic CORT-induced maladaptive reward and motivation behaviors.

Chronic corticosterone shifts effort-related choice behavior in male mice.

RATIONALE: Effort-related choice tasks are used to study aspects of motivation in both rodents and humans (Der-Avakian and Pizzagalli Biol Psychiatry 83(11):932-939, 2018). Various dopaminergic manipulations and antidepressant treatments can shift responding to these tasks (Randall et al. Int J Neuropsychopharmacol 18(2), 2014; Yohn et al. Psychopharmacology 232(7):1313-1323, 2015). However, while chronic stress can precipitate mood disorders in humans, there is relatively little known about whether chronic stress elicits maladaptive behaviors in rodent effort-related choice tasks. OBJECTIVES: Chronic corticosterone (CORT) elicits an increase in negative maladaptive behaviors in male mice (David et al. Neuron 62(4):479-493, 2009; Gourley et al. Biol Psychiatry 64(10):884-890, 2008; Olausson et al. Psychopharmacology 225(3):569-577, 2013). We hypothesized that chronic CORT administration to male mice would reduce motivation for a higher effort, higher reward option, and shift responding to a less effortful, but a lesser reward. METHODS: Adult male C57BL/6J mice were administered either vehicle (n = 10) or CORT (n = 10) (~ 9.5 mg/kg/day) in their drinking water for 4 weeks, and then throughout all behavioral experiments (15 weeks total), and were tested in a Y-Maze barrier task and a fixed ratio concurrent (FR/chow) choice task. RESULTS: Chronic CORT reduced Y-maze HR arm choice when more effort was required to obtain the 4 food pellets (15-cm barrier in the high-reward (HR) arm, p < 0.001; 20-cm barrier in HR arm, p < 0.001) and shifted choice to the low reward (LR) arm where only 2 pellets were available. Chronic CORT also reduced lever pressing for food pellets in FR30/chow sessions of the concurrent choice task (p = 0.009), without impacting lab chow consumed. CONCLUSIONS: Chronic stress induces maladaptive shifts in effort-related choice behavior in the Y-maze barrier task in male mice. Furthermore, males subjected to chronic CORT administration show reduced lever pressing in FR30/chow sessions where lab chow is concurrently available. These data demonstrate that chronic corticosterone reduces motivation to work for and obtain a highly rewarding reinforcer when a lesser reinforcer is concurrently available.

Chronic corticosterone administration induces negative valence and impairs positive valence behaviors in mice.

Behavioral approaches utilizing rodents to study mood disorders have focused primarily on negative valence behaviors associated with potential threat (anxiety-related behaviors). However, for disorders such as depression, positive valence behaviors that assess reward processing may be more translationally valid and predictive of antidepressant treatment outcome. Chronic corticosterone (CORT) administration is a well-validated pharmacological stressor that increases avoidance in negative valence behaviors associated with anxiety1-4. However, whether chronic stress paradigms such as CORT administration also lead to deficits in positive valence behaviors remains unclear. We treated male C57BL/6J mice with chronic CORT and assessed both negative and positive valence behaviors. We found that CORT induced avoidance in the open field and NSF. Interestingly, CORT also impaired instrumental acquisition, reduced sensitivity to a devalued outcome, reduced breakpoint in progressive ratio, and impaired performance in probabilistic reversal learning. Taken together, these results demonstrate that chronic CORT administration at the same dosage both induces avoidance in negative valence behaviors associated with anxiety and impairs positive valence behaviors associated with reward processing. These data suggest that CORT administration is a useful experimental system for preclinical approaches to studying stress-induced mood disorders.