Noradrenergic Modulation of an Amygdalo-thalamic Circuit

Emotional and cognitive processing rely on communication between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). The BLA regulates mPFC both directly and indirectly via the medial sub-division of the medial dorsal thalamus (MDm). Although the BLA projection to MDm has been established anatomically, less is known about the functional properties of this synapse. Here, using patch-clamp electrophysiology and optogenetics in ex vivo mouse brain slices, we found that BLA neurons make potent synaptic connections onto MDm neurons capable of evoking action potentials. The site of this BLA input overlaps with strong innervation from locus coeruleus norepinephrine (NE) axons. We found that NE acts via 2-adrenergic receptors to strongly reduce excitatory postsynaptic currents from BLA to MDm. NE also decreases the release probability of BLA axon terminals through a presynaptic mechanism. Postsynaptically, NE depolarizes MDm neurons and increases their tonic firing rates. These findings show that NE, whose levels are elevated during arousal and stress, can suppress transmission of affective information from BLA into MDm, thereby blunting this potent indirect pathway from BLA to mPFC. SIGNIFICANCE STATEMENTPrevious anatomical studies have suggested the importance of amygdala input to the limbic thalamus. Here, using ex vivo electrophysiology and optogenetics in adult mice, we characterize the excitatory input from basolateral amygdala to mediodorsal thalamus, revealing the potency and physiological characteristics of this input. Further, we show that the stress-related neuromodulator, norepinephrine, binds to the 2-adrenergic receptor to significantly dampen transmission of affective information carried by this synapse. These findings improve our understanding of key circuits involved in emotional processing and provide insight on how stress-induced neuromodulation may change circuit function, which is relevant to stress-related neuropsychiatric disorders such as depression, anxiety, schizophrenia, and PTSD.