Finnell et al LC-NE neuroinflammation BBI Supplement.docx

Supplemental Section of our accepted Manuscript:

Exposure
to psychosocial stress is known to precipitate the emergence of stress related
psychiatric disorders such as depression and anxiety. While mechanisms by which
this occurs remain largely unclear, recent evidence points towards a causative
role for inflammation. Neurotransmitters, such as norepinephrine (NE) are
capable of regulating expression of proinflammatory cytokines and thus may
contribute to the emergence of stress-related disorders. The locus coeruleus
(LC) is the major source of norepinephrine (NE) to the brain and therefore the
current study utilized N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), an
LC selective noradrenergic neurotoxin, to determine the discrete involvement of
the LC-NE system in social defeat-induced inflammation in LC projection regions
including the central amygdala (CeA), dorsal raphe (DR) and plasma. In the
current study, rats were exposed to brief social defeat or control
manipulations on 5 consecutive days. To determine whether a history of social
defeat enhanced or “primed” the inflammatory response to a subsequent defeat
exposure, all rats regardless of stress history were exposed to an acute social
defeat challenge immediately prior to tissue collection. As anticipated, prior
history of social defeat primed inflammatory responses in the plasma and CeA
while neuroinflammation in the DR was markedly reduced. Notably, DSP-4
treatment suppressed stress-induced circulating inflammatory cytokines
independent of prior stress history. In contrast, neuroinflammation in the CeA
and DR were greatly augmented selectively in DSP-4 treated rats with a history
of social defeat. Together these data highlight the dichotomous nature of NE in
stress-induced inflammatory priming in the periphery and the brain and directly
implicate the LC-NE system in these processes.