Cortical Circuits of Callosal GABAergic Neurons.

Anatomical studies have shown that the majority of callosal axons are glutamatergic. However, a small proportion of callosal axons are also immunoreactive for glutamic acid decarboxylase, an enzyme required for gamma-aminobutyric acid (GABA) synthesis and a specific marker for GABAergic neurons. Here, we test the hypothesis that corticocortical parvalbumin-expressing (CC-Parv) neurons connect the two hemispheres of multiple cortical areas, project through the corpus callosum, and are a functional part of the local cortical circuit. Our investigation of this hypothesis takes advantage of viral tracing and optogenetics to determine the anatomical and electrophysiological properties of CC-Parv neurons of the mouse auditory, visual, and motor cortices. We found a direct inhibitory pathway made up of parvalbumin-expressing (Parv) neurons which connects corresponding cortical areas (CC-Parv neurons → contralateral cortex). Like other Parv cortical neurons, these neurons provide local inhibition onto nearby pyramidal neurons and receive thalamocortical input. These results demonstrate a previously unknown long-range inhibitory circuit arising from a genetically defined type of GABAergic neuron that is engaged in interhemispheric communication.

A Layer-specific Corticofugal Input to the Mouse Superior Colliculus.

In the auditory cortex (AC), corticofugal projections arise from each level of the auditory system and are considered to provide feedback "loops" important to modulate the flow of ascending information. It is well established that the cortex can influence the response of neurons in the superior colliculus (SC) via descending corticofugal projections. However, little is known about the relative contribution of different pyramidal neurons to these projections in the SC. We addressed this question by taking advantage of anterograde and retrograde neuronal tracing to directly examine the laminar distribution, long-range projections, and electrophysiological properties of pyramidal neurons projecting from the AC to the SC of the mouse brain. Here we show that layer 5 cortico-superior-collicular pyramidal neurons act as bandpass filters, resonating with a broad peak at ∼3 Hz, whereas layer 6 neurons act as low-pass filters. The dissimilar subthreshold properties of layer 5 and layer 6 cortico-superior-collicular pyramidal neurons can be described by differences in the hyperpolarization-activated cyclic nucleotide-gated cation h-current (Ih). Ih also reduced the summation of short trains of artificial excitatory postsynaptic potentials injected at the soma of layer 5, but not layer 6, cortico-superior-collicular pyramidal neurons, indicating a differential dampening effect of Ih on these neurons.

An inhibitory corticostriatal pathway.

Anatomical and physiological studies have led to the assumption that the dorsal striatum receives exclusively excitatory afferents from the cortex. Here we test the hypothesis that the dorsal striatum receives also GABAergic projections from the cortex. We addressed this fundamental question by taking advantage of optogenetics and directly examining the functional effects of cortical GABAergic inputs to spiny projection neurons (SPNs) of the mouse auditory and motor cortex. We found that the cortex, via corticostriatal somatostatin neurons (CS-SOM), has a direct inhibitory influence on the output of the striatum SPNs. Our results describe a corticostriatal long-range inhibitory circuit (CS-SOM inhibitory projections → striatal SPNs) underlying the control of spike timing/generation in SPNs and attributes a specific function to a genetically defined type of cortical interneuron in corticostriatal communication.

Callosal projections drive neuronal-specific responses in the mouse auditory cortex.

In the auditory cortex (AC), interhemispheric communication is involved in sound localization processes underlying spatial hearing. However, the neuronal microcircuits recruited by the callosal projections are unknown. We addressed this fundamental question by taking advantage of optogenetics and examining directly the functional effects of interhemispheric inputs to specific pyramidal neurons in layer 5 of the mouse AC, defined by their output as either corticocortical (CCort) or corticocollicular (CCol). We found that callosal projections suppress the activity of CCort pyramidal neurons, but facilitate firing of CCol pyramidal neurons. This difference is mechanistically explained by callosal activation of fast-spiking parvalbumin-expressing interneurons (FS-PARV), which provide selective inhibition to CCort pyramidal neurons. Our results establish two distinct previously unknown cortical circuits underlying either callosal suppression (callosal projections → FS-PARV → CCort) or facilitation (callosal projections → CCol) of projecting neurons in layer 5 of the AC and attribute a specific function to a genetically defined type of interneuron in interhemispheric communication.

Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice.

Supratherapeutic doses of the analgesic acetaminophen (paracetomol) are reported to promote social behavior in Swiss mice. However, we hypothesized that it might not promote sociability in other strains due to cannabinoid CB(1) receptor-mediated inhibition of serotonin (5-HT) transmission in the frontal cortex. We examined the effects of acetaminophen on social and repetitive behaviors in comparison to a cannabinoid agonist, WIN 55,212-2, in two strains of socially-deficient mice, BTBR and 129S1/SvImJ (129S). Acetaminophen (100mg/kg) enhanced social interactions in BTBR, and social novelty preference and marble burying in 129S at serum levels of ≥70 ng/ml. Following acetaminophen injection or sociability testing, anandamide (AEA) increased in BTBR frontal cortex, while behavior testing increased 2-arachidonyl glycerol (2-AG) levels in 129S frontal cortex. In contrast, WIN 55,212-2 (0.1mg/kg) did not enhance sociability. Further, we expected CB(1)-deficient (+/-) mice to be less social than wild-type, but instead found similar sociability. Given strain differences in endocannabinoid response to acetaminophen, we compared cortical CB(1) and 5-HT(1A) receptor density and function relative to sociable C57BL/6 mice. CB(1) receptor saturation binding (Bmax=958±117 fmol/mg protein), and affinity for [(3)H] CP55,940 (K(D)=3±0.8 nM) was similar in frontal cortex among strains. CP55,940-stimulated [(35)S] GTPγS binding in cingulate cortex was 136±12, 156±22, and 75±9% above basal in BTBR, 129S and C57BL/6 mice. The acetaminophen metabolite para-aminophenol (1 µM) failed to stimulate [(35)S] GTPγS binding. Hence, it appears that other indirect actions of acetaminophen, including 5-HT receptor agonism, may underlie its sociability promoting properties outweighing any CB(1) mediated suppression by locally-elevated endocannabinoids in these mice.