Neuromodulatory organization in the developing rat somatosensory cortex

Abstract

The vast majority of cortical synapses are found in the neuropil which is implicated in multiple and diverse functions underlying brain computation. Unraveling the organizing principles of the cortical neuropil requires an intricate characterization of synaptic connections established by excitatory and inhibitory axon terminals, of intrinsic and extrinsic origin and from ascending projections that govern the function of cortical microcircuits through the release of neuromodulators either through point-to-point chemical synapses or diffuse volume transmission (VT). Even though neuromodulatory release has been studied for almost a century it is still not clear if one modality prevails upon the other. The hindlimb representation of the somatosensory cortex (HLS1) of two-week old Wistar rats has served as a model system to dissect the microcircuitry of neurons and their synaptic connections. In the present study, we quantified the fiber length per cortical volume and the density of varicosities for cholinergic, catecholaminergic and serotonergic neuromodulatory systems in the cortical neuropil using immunocytochemical staining and stereological techniques. Acquired data were integrated into a novel computational framework to reconcile the specific modalities and predict the effects of neuromodulatory release in shaping neocortical network activity. We predict that acetylcholine (ACh), dopamine (DA), serotonin (5-HT) release desynchronizes cortical activity by inhibiting slow oscillations (delta range), and that 5-HT triggers faster oscillations (theta). Moreover, we found that high levels (>40%) of neuromodulatory VT are sufficient to induce network desynchronization, but also that combining volume release with synaptic inputs leads to more robust and stable effects, meaning that lower levels of VT are needed to achieve the same outcome (10%).

Acetylcholine Neurons Become Cholinergic during Three Time Windows in the Developing Mouse Brain

“…ACh neurons and nAChRs can be detected from an early time point in the embryonic brain but the findings vary based on the experimental conditions ( Cimino, 1995 ; Jaarsma et al, 1997 ; Zhang, 1998 ; Abreu-Villaca et al, 2011 ; Zhang et al, 2016 ; Broide et al, 2019 ; Abbasi et al, 2020 ; Alzu’bi et al, 2020 ; Colangelo et al, 2022 ; Saad et al, 2022 ). While it has been shown that hindbrain CN neurons are born approximately at E9, basal forebrain ACh neuron between E10 and E13.5, and neurons in the habenula between E14 and E18, the date of birth does not explain when ACh neurons become cholinergic ( Finlay and Darlington, 1995 ; Allaway et al, 2020 ; Ananth et al, 2023 ; Funato et al, 2000 ).…”

“…Additionally, it is essential to study the location and composition of cholinergic synapses, nicotinic, as well as muscarinic receptors at different developmental time points similar to recent research at the neuromuscular junction ( York and Zheng, 2017 ; Badawi and Nishimune, 2018 ). Besides, the development of the cholinergic system should be assessed in relationship with other neurotransmitter or neuromodulator systems on a whole-brain level ( Colangelo et al, 2022 ). Lastly, ACh neurons coexpress GABAergic markers during development, and GABA cotransmission is important for mature brain function ( von Bartheld and Rubel, 1989 ; Goral et al, 2022 ; Granger et al, 2023 ; Lozovaya et al, 2023 ).…”

“…Despite recent breakthroughs, such as reconstruction of individual ACh neuron projection fields, the generation of whole-brain atlases of ACh neurons or input/output mapping to/from the basal forebrain ACh neurons, and RNA expression patterns in the developed brain, very little progress has been made regarding a comprehensive assessment of developmental changes in ACh neurons ( Oh et al, 2014 ; Wu et al, 2014 ; Gielow and Zaborszky, 2017 ; Li et al, 2018 ; Cizeron, 2020 ; Wang et al, 2020 ; Tomas-Roca et al, 2022 ; Gamage et al, 2023 ). While there is a trove of literature about nAChR mRNA or protein level changes in many brain regions in the pre- or postnatal rodent brain, there is little data about how onset of cholinergic signaling overlaps with the nAChR expression patterns in these brain regions ( Cimino, 1995 ; Jaarsma et al, 1997 ; Zhang, 1998 ; Abreu-Villaca et al, 2011 ; Zhang et al, 2016 ; Broide et al, 2019 ; Abbasi et al, 2020 ; Alzu’bi et al, 2020 ; Colangelo et al, 2022 ; Saad et al, 2022 ).…”