This Week in The Journal

Amygdala Targets in Prefrontal Cortex

Laura M. McGarry and Adam G. Carter

The prefrontal cortex (PFC) is active when previous experience is used to guide behavioral choices in situations potentially involving reward or punishment. This occurs, for example, after fear conditioning, when a cue or context previously paired with a foot shock elicits freezing behavior. The PFC is activated when the conditioned stimulus is encountered, and it is necessary for extinguishing fear responses when conditioned stimuli no longer predict shock (Do-Monte et al. J Neurosci 2015 35:3607). This experience-dependent regulation of fear responses depends on reciprocal connections between the PFC and the amygdala.

To understand how amygdala–PFC connections influence fear responses, one must know which cell types are activated by projections to each area. Previous work has shown that glutamatergic projections from the amygdala to the PFC innervate parvalbumin-expressing (PV) inhibitory interneurons, as well as pyramidal neurons that project back to the amygdala. Whether other cell types receive direct input from the amygdala and which cells receive feed-forward inhibition via PV interneurons remained unknown. Therefore, McGarry and Carter used optogenetics to activate amygdala axon terminals while recording from labeled PFC neurons in mouse brain slices.

Amygdala axons overlapped with the dendrites of corticoamygdala and corticostriatal projection neurons in layer 2 of PFC. Stimulating amygdala axons evoked EPSCs followed by IPSCs in both of these neuronal classes, but the PSCs were larger in corticoamygdala neurons. Amygdala axons also made monosynaptic connections with PV and somatostatin-expressing (SOM) interneurons. While EPSCs in SOM neurons were similar in amplitude to those in corticoamygdala neurons, those in PV interneurons were larger. Consequently, low-intensity stimulation of amygdala axons evoked EPSCs only in PV neurons. Short-term plasticity at amygdala–PFC synapses also differed across postsynaptic neuron classes: whereas EPSCs in corticoamygdala, corticostriatal, and PV neurons decreased in amplitude during spike trains, EPSCs in SOM interneurons grew larger. Thus, low-intensity stimulus trains initially evoked spikes only in PV neurons, but later recruited SOM neurons. Finally, optogenetic stimulation of PV or SOM interneurons evoked IPSCs in both corticoamygdala and corticostriatal neurons, with larger IPSCs in corticoamygdala neurons.

These results suggest that projections from the basolateral amygdala to PFC layer 2 evoke a short period of excitation followed by feed-forward inhibition of corticoamygdala and corticostriatal projection neurons. This may ensure that PFC projection neurons are active for just a brief period, making communication more precise and facilitating synaptic plasticity required for extinction learning.

How Cholinergic Neurons Inhibit Striatal Projection Neurons

Thomas W. Faust, Maxime Assous, James M. Tepper, and Tibor Koós

(see pages 9505–9511)

The striatum shapes motor function via the output of medium spiny projection neurons (SPNs). The activity of these neurons is regulated partly by tonically active cholinergic interneurons. Acetylcholine influences SPN activity not only directly, via muscarinic receptors, but also indirectly, via muscarinic and nicotinic receptors located on the terminals of dopaminergic and glutamatergic afferents and on local GABAergic interneurons. Activation of nicotinic receptors in the striatum elicits fast and slow GABAergic IPSCs in SPNs, but whether this effect is mediated primarily by GABAergic interneurons or GABA co-released with dopamine from nigrostriatal afferents has been unclear.

Optical stimulation of cholinergic interneurons (blue bar at top) normally produces IPSCs in SPNs (gray individual traces and black average trace). Simultaneous optical inhibition of GABAergic interneurons (yellow bar at top) reduces this inhibition (yellow individual traces and red average trace). See Faust et al. for details.

To answer this question, Faust et al. created double-transgenic mice that expressed channelrhodopsin in cholinergic interneurons and halorhodopsin in subpopulations of GABAergic interneurons. Stimulating cholinergic interneurons in brain slices with blue light elicited spiking in GABAergic interneurons and produced large IPSCs in SPNs. When slices were stimulated simultaneously with blue and yellow light, however, spiking was suppressed in GABAergic interneurons, and the amplitude of both the fast and slow components of IPSCs in SPNs were reduced. The amount of reduction varied across cells, however, with some SPNs showing no decrease in either component and others showing 80–90% reduction.

These results suggest that GABAergic interneurons that express holorhodopsin in these mice are the main source of acetylcholine-induced inhibition in most SPNs. One subtype of interneurons expressing holorhodopsin is neurogliaform cells, which have previously been shown to mediate slow inhibition of SPNs. The subpopulation mediating the fast component remains a mystery, however. Furthermore, whether the residual IPSCs are evoked primarily by dopaminergic neurons or untargeted subpopulations of striatal interneurons—or a combination of these sources—remains unclear. Similar use of double transgenic mice that allow inhibition of other neuronal classes should provide answers to these questions.