Layer-specific pyramidal neuron properties underlie diverse anterior cingulate cortical motor and limbic networks

Abstract

The laminar cellular and circuit mechanisms by which the anterior cingulate cortex (ACC) exerts flexible control of motor and affective information for goal-directed behavior have not been elucidated. Using multimodal tract-tracing, in vitro patch-clamp recording and computational approaches in rhesus monkeys (M. mulatta), we provide evidence that specialized motor and affective network dynamics can be conferred by layer-specific biophysical and structural properties of ACC pyramidal neurons targeting two key downstream structures —the dorsal premotor cortex (PMd) and the amygdala (AMY). AMY-targeting neurons exhibited significant laminar differences, with L5 more excitable (higher input resistance and action potential firing rates) than L3 neurons. Between-pathway differences were found within L5, with AMY-targeting neurons exhibiting greater excitability, apical dendritic complexity, spine densities, and diversity of inhibitory inputs than PMd-targeting neurons. Simulations using a pyramidal-interneuron network model predict that these layer- and pathway-specific single-cell differences contribute to distinct network oscillatory dynamics. L5 AMY-targeting networks are more tuned to slow oscillations well-suited for affective and contextual processing timescales, while PMd-targeting networks showed strong beta/gamma synchrony implicated in rapid sensorimotor processing. These findings are fundamental to our broad understanding of how layer-specific cellular and circuit properties can drive diverse laminar activity found in flexible behavior.

Comparative Features of Calretinin, Calbindin and Parvalbumin Expressing Interneurons in Mouse and Monkey Primary Visual and Frontal Cortices

“…Whole brain tissue was fixed and extracted from monkeys using our 2-stage perfusion procedure described previously (Medalla et al, 2021; Medalla et al, 2017). Briefly, monkeys were sedated with ketamine hydrochloride (10 mg/kg) and subsequently anesthetized with sodium pentobarbital (15 mg/kg, to effect).…”

“…A total of 386 cells were reconstructed (an average of 30 cells per area and CaBP+ cell type), with soma-to-pia distance of cells that were within the boundaries of L2-3 as follows: Cells within 250-500 µm deep from the pia for monkey V1, 200-700 µm deep for monkey LPFC, and 200-400 µm deep for mouse V1 and FC (Gilman et al, 2017; Medalla & Barbas; Van De Werd et al, 2010). The somata and visible dendrites of neurons were reconstructed in 3D using Neurolucida 360 (NL360) version 2019.1.1 (MBF Bioscience) as described in our previous work (Guillamon- Vivancos et al, 2019; Medalla et al, 2021). All somata were automatically detected and dendrites were manually traced throughout the z-stack.…”

Comparative features of calretinin, calbindin, and parvalbumin expressing interneurons in mouse and monkey primary visual and frontal cortices

“…Whole brain tissue was fixed and extracted from monkeys using our two-stage perfusion procedure described previously (Medalla et al, 2021(Medalla et al, , 2017. Briefly, monkeys were sedated with ketamine hydrochloride (10 mg/kg) and subsequently anesthetized with sodium pentobarbital (15 mg/kg, to effect).…”

“…A total of 386 cells were reconstructed (an average of 30 cells per area and CaBP+ cell type), with soma‐to‐pia distance of cells that were within the boundaries of L2–3 as follows: Cells within 250–500 μm deep from the pia for monkey V1, 200–700 μm deep for monkey LPFC, and 200–400 μm deep for mouse V1 and FC (Gilman et al., 2017; Medalla & Barbas, 2010; Van De Werd et al., 2010). The somata and visible dendrites of neurons were reconstructed in 3D using Neurolucida 360 (NL360) version 2019.1.1 (MBF Bioscience) as described in our previous work (Guillamon‐Vivancos et al., 2019; Medalla et al., 2021). All somata were automatically detected and dendrites were manually traced throughout the z ‐stack.…”

Biophysical modeling of frontocentral ERP generation links circuit-level mechanisms of action-stopping to a behavioral race model

“…Efferent projections from mPFC to thalamic and/or cortical targets are also important to consider, as these projections provide possibilities for re-emergent thalamocortical signaling (which we assume produces the second proximal drive generating the P3 in our models) and ultimately contribute to network activity supporting the Stop process during successful action-stopping. Projections from Layer 2/3 and 5 of mPFC may target dorsal motor areas such as the premotor or pre-supplementary motor areas (Medalla et al, 2022), and Layer 5 and Layer 6 (which is not explicitly modeled in HNN currently) neurons are known to project back to both higher– (i.e., MD/AM) and lower-order (i.e., VA) thalamic nuclei, respectively (Domesick, 1969; Zikopoulos & Barbas, 2007), which could contribute to re-emergent thalamocortical signaling (see Figure 7 ).…”