Forebrain GABAergic projections from the dorsal raphe nucleus identified by using GAD67–GFP knock-in mice

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The dorsal raphe nucleus (DR) contains serotonergic (5-HT) neurons that project widely throughout the forebrain. These forebrain regions also receive innervation from non–5-HT neurons in the DR. One of the main groups of non–5-HT neurons in the DR is γ-aminobutyric acid (GABA)ergic, but their projections are poorly understood due to the difficulty of labeling these neurons immunohistochemically. To identify GABAergic projection neurons within the DR in the current study, we used a knock-in mouse line in which expression of green fluorescent protein (GFP) is controlled by the glutamic acid decarboxylase (GAD)67 promotor. Projections of GAD67–GFP neurons to the prefrontal cortex (PFC), nucleus accumbens (NAC), and lateral hypothalamus (LH) were evaluated by using retrograde tract tracing. The location of GAD67–GFP neurons projecting to each of these areas was mapped by rostrocaudal and dorsoventral location within the DR. Overall, 16% of DR neurons projecting to either the PFC or NAC were identified as GAD67–GFP neurons. GAD67–GFP neurons projecting to the PFC were most commonly found ventrally, in the rostral two-thirds of the DR. NAC-projecting GAD67–GFP neurons had an overlapping distribution that extended dorsally. GAD67–GFP neurons made a larger contribution to the projection of the DR to the LH, accounting for 36% of retrogradely labeled neurons, and were widespread throughout the DR. The current data indicate that DR GABAergic neurons not only may have the capacity to influence local network activity, but also make a notable contribution to DR output to multiple forebrain targets.

The current study shows that GABAergic neurons in the dorsal raphe display trends for selective projections to the forebrain including the prefrontal cortex, nucleus accumbens, and lateral hypothalamus. These findings suggest that a notable fraction of the ascending projections from the dorsal raphe arise from GABAergic neurons. The results also indicate that GABAergic neurons might have the capacity to both influence local network activity and contribute to forebrain output. For abbreviations, see list in text.

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