Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519–11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long-projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models.

it has been a long-standing belief that behavior is modulated by cortical control over subcortical structures exclusively through excitatory glutamatergic projections. There has been a general consensus that inhibitory GABAergic neurons in the cortex participate mainly in local microcircuits. For example, GABAergic interneurons in the medial prefrontal cortex (mPFC) compose local microcircuits that shape prefrontal coding of fear expression (Courtin et al. 2014). Generally, models of top-down cortical control involve excitatory projections to downstream regions. In such cases, behavioral regulation depends on whether mPFC fibers selectively target excitatory or inhibitory neurons. This is the case of the mPFC-amygdala model proposed for fear regulation: the prelimbic prefrontal cortex (PL) drives fear by its excitatory projections to excitatory neurons in the basolateral amygdala (BLA), whereas the infralimbic prefrontal cortex (IL) inhibits fear by its excitatory projections to GABAergic intercalated cells (ITCs) in the amygdala (Sotres-Bayon and Quirk 2010).

Other models involve mPFC projections to distinct subregions that compete for behavioral control. In the reward system, PL excitatory neurons drive reward seeking through the nucleus accumbens (NAcc) core, whereas IL excitatory neurons inhibit reward seeking through its connections with the NAcc shell (Peters et al. 2009). However, until now, there was no functional evidence of prefrontal inhibitory projections to downstream regions that could directly influence behavior. A recent study by Lee et al. (2014) elegantly characterized long-projecting GABAergic neurons in the mPFC and tested whether these projections to the NAcc can modulate behavior.

The authors identified cortical GABAergic projections by infusing a viral vector containing channelrhodopsin (AAV-DIO-ChR2-EYFP) into the mPFC of Dlxi12b-Cre mice to selectively target GABAergic neurons. Labeling of GABAergic mPFC fibers was detected at several downstream regions including NAcc and BLA. Using whole cell recordings in NAcc, the authors found that optogenetic activation of mPFC ChR2-containing terminals in NAcc elicited inhibitory postsynaptic currents (IPSCs) in NAcc neurons. Blocking GABA A , but not glutamate, receptors in NAcc abolished the IPSCs, indicating that these mPFC long-range projections are GABAergic. Previous studies have shown that activation of GABAergic projections from subcortical regions to NAcc elicit aversion. Thus the authors tested whether cortical GABAergic projections could also mediate aversive responses. Indeed, they found that mice refrained from entering a chamber paired with stimulation of GABAergic mPFC fibers in NAcc, suggesting that long-range GABAergic neurons in mPFC can drive aversion through its projections to NAcc.

These findings are timely given that many research groups have investigated how cortical glutamatergic projections modulate behavior, overlooking a potential role for cortical GABAergic projections. All previous behavioral studies on cortical GABAergic neurons have focused exclusively on local inhibitory circuits. The study by Lee et al. (2014) is the first to demonstrate that cortical GABAergic projections to downstream targets can modulate aversive responses. Going forward, future studies need to characterize the potential role of cortical GABAergic projections in the neuropathology of mental illness.

GRANTS This work was supported by National Institutes of Health Grants MH102968 (to C. Bravo-Rivera) MH105039 (to J. Rodriquez-Romaguera), MH106332 (to L. E. Rosas-Vidal), and University of Puerto Rico School of Medicine Research Initiative for Scientific Enhancement Fellowship GM061838 (to H. Bravo-Rivera and K. Quiñones-Laracuente).

DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS C.B.-R., M.M.D., C.R.-O., J.R.-R., L.E.R.-V., H.B.-R., K.Q.-L., and F.H.D.-M. prepared figures; C.B.-R., M.M.D., C.R.-O., J.R.-R., L.E.R.-V., H.B.-R., K.Q.-L., and F.H.D.-M. drafted manuscript; C.B.-R., M.M.D., C.R.-O., J.R.-R., L.E.R.-V., H.B.-R., K.Q.-L., and F.H.D.-M. edited and revised manuscript; C.B.-R., M.M.D., C.R.-O., J.R.-R., L.E.R.-V., H.B.-R., K.Q.-L., and F.H.D.-M. approved final version of manuscript.