Properties and modulation of excitatory inputs to the locus coeruleus

Excitatory inputs drive burst firing of locus coeruleus (LC) noradrenaline (NA) neurons in response to a variety of stimuli. Though a small number of glutamatergic LC afferents have been investigated, the overall landscape of these excitatory inputs is largely unknown. The current study used an optogenetic approach to isolate three glutamatergic afferents: the prefrontal cortex (PFC), lateral hypothalamus (LH) and periaqueductal grey (PAG). AAV5-DIO-ChR2 was injected into each region in male and female CaMKII-Cre mice and the properties of excitatory inputs on LC-NA cells were measured. Notably we found differences among these inputs. First, the pattern of axonal innervation differed between inputs such that LH afferents were concentrated in the posterior portion of the LC-NA somatic region while PFC afferents were denser in the medial dendritic region. Second, basal intrinsic properties varied for afferents, with LH inputs having the highestconnectivity and the largest amplitude excitatory postsynaptic currents while PAG inputs had the lowest initial release probability. Third, while orexin and oxytocin had minimal effects on any input, dynorphin strongly inhibited excitatory inputs originating from the LH and PAG, and corticotrophin releasing factor (CRF) selectively inhibited inputs from the PAG. Overall, these results demonstrate that individual afferents to the LC have differing properties, which may contribute to the modularity of the LC and its ability to mediate various behavioural outcomes.