Prefrontal modulation of anxiety through a lens of noradrenergic signaling

Abstract

Anxiety disorders are the most common class of mental illness in the U.S., affecting 40 million individuals annually. Anxiety is an adaptive response to a stressful or unpredictable life event. Though evolutionarily thought to aid in survival, excess intensity or duration of anxiogenic response can lead to a plethora of adverse symptoms and cognitive dysfunction. A wealth of data has implicated the medial prefrontal cortex (mPFC) in the regulation of anxiety. Norepinephrine (NE) is a crucial neuromodulator of arousal and vigilance believed to be responsible for many of the symptoms of anxiety disorders. NE is synthesized in the locus coeruleus (LC), which sends major noradrenergic inputs to the mPFC. Given the unique properties of LC-mPFC connections and the heterogeneous subpopulation of prefrontal neurons known to be involved in regulating anxiety-like behaviors, NE likely modulates PFC function in a cell-type and circuit-specific manner. In working memory and stress response, NE follows an inverted-U model, where an overly high or low release of NE is associated with sub-optimal neural functioning. In contrast, based on current literature review of the individual contributions of NE and the PFC in anxiety disorders, we propose a model of NE level- and adrenergic receptor-dependent, circuit-specific NE-PFC modulation of anxiety disorders. Further, the advent of new techniques to measure NE in the PFC with unprecedented spatial and temporal resolution will significantly help us understand how NE modulates PFC function in anxiety disorders.

Gating of Memory to Behavior by the Locus Coeruleus

“…Here, the relevant sensory cues are not restricted to what is encountered during conditioning/learning, but instead can be generalized, such as to the same sensory modality. This notion of a temporary vigilance/alertness state is consistent with the LC/NE associated with vigilance and anxiety (Poe et al, 2020;Berrocoso et al, 2022;Bouras et al, 2023). We must emphasize that the neuromodulators released during this time window mostly target the memory-elicited behavior rather than the memory itself.…”

Antidepressant and Anxiolytic Effects of L-Methionine in the WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy

“…Moreover, NA modulated neuronal activity and is essential for the "optimal" functioning of the prefrontal cortex involved in the regulation of the arousal level, decision making, working memory, cognition, and attention. When the "optimal" level of NA release in the prefrontal cortex is disrupted, impairments of the top-down control over other brain regions occur, leading to behavioral disorders; in particular, increased anxiety [62]. The hypothalamus and hippocampus are related to some aspects of depression [63].…”

Large nesting expression in deer mice remains stable under conditions of visual deprivation despite heightened limbic involvement: Perspectives on compulsive‐like behavior

“…However, since antidepressants with a noradrenergic mechanism of action are mostly ineffective in the treatment of OCD (Kellner, 2022), some background is needed. Under resting state conditions in healthy subjects, moderate concentrations of frontal‐cortical noradrenaline, which is primarily released from noradrenergic projections originating in the locus coeruleus (LC), inhibit amygdalar reactivity, and thus also anxiety‐ and fear‐related processing in the limbic system (Bouras, 2023; Coley et al., 2021). This allows for normal executive functions to take precedent.…”

“…However, once specific sensory or emotional stimuli activate the limbic system, a transient increase in limbic noradrenaline release exerts inhibitory control over prefrontal‐cortical processing (McCall et al., 2015) and so facilitates an optimal degree of arousal, attention, and fight‐or‐flight readiness (Arnsten, 2011). Importantly, patients suffering from anxiety disorders consistently show limbic hyperactivation (Boehme et al., 2014), which may point to a lower anxiety sensitivity threshold or alternatively, a loss in top‐down frontal‐cortical control over limbic activation (Bouras, 2023); this also explains why alpha (α) 1‐ and beta (β) adrenoceptor activation contributes to the manifestation of anxiety‐ and fear‐related symptoms post‐trauma (Gazarini et al., 2013).…”