Noradrenergic inputs to the basolateral amygdala have bidirectional effects on coping behavior and neuronal activity in mice

Norepinephrine (NE) signaling is disrupted in stress disorders, with insufficient NE signaling implicated in major depressive disorder and hyperactive NE signaling associated with post-traumatic stress disorder, suggesting that adequate mood regulation requires optimal NE levels. The basolateral amygdala (BLA) is a hub for stress processing and receives dense noradrenergic innervation from the locus coeruleus (LC), the primary noradrenergic nucleus in the brain. The relationship between LC activity and cognitive/behavioral function during fear conditioning has been described as an inverted U, in which moderate LC activity, and subsequent NE release, is required for adaptive coping to threats, while hyperactive LC-NE signaling drives maladaptive behavioral responses. We used fiber photometry to measure NE signaling in the mouse BLA during acute behavioral responses to escapable and inescapable stressors, and then used an optogenetic approach to stimulate the noradrenergic terminals in the BLA at different frequencies to evaluate effects on coping behavior and cFos expression in the LC-BLA circuit. We found that low-frequency stimulation of the circuit inhibited both passive coping and BLA neuronal activity, while high-frequency stimulation had the opposite effect; the behavioral effects were not mediated by sex, but the cFos effects were specific to males. This study represents an expansion of the inverted U framework to encompass LC-BLA signaling driving acute behavioral responses to stress. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/677150v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1b642a7org.highwire.dtl.DTLVardef@d20eedorg.highwire.dtl.DTLVardef@d22aa7org.highwire.dtl.DTLVardef@1ee4291_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBLA NE levels signal behavioral transitions between coping responses to stress C_LIO_LILow-frequency stimulation of BLA NE terminals inhibits passive coping and BLA cFos C_LIO_LIHigh-frequency stimulation of BLA NE terminals promotes passive coping and BLA cFos C_LIO_LIBehavioral effects are similar across sexes, but cFos alterations are male- specific C_LI