The spineless origins of prefrontal cortex dysfunction and psychiatric disorders

Fundamental research into early circuits of the neocortex provides insight into the etiology of mental illness. In this issue of Neuron, Chini et al. (2020) probe the consequences of combined genetic and environmental perturbation on emergent network activity in the prefrontal cortex, identifying a window for possible intervention

Modulation by 5-hydroxytryptamine of nicotinic acetylcholine responses recorded from an identified cockroach (Periplaneta americana) motoneuron

Recordings from the soma of the cockroach (Periplaneta americana) fast coxal depressor motoneuron (D-f) were made while acetylcholine (ACh) was regularly pressure-applied locally from a micropipette. The modulatory effects upon these nicotinic ACh responses of bath-applied 5-hydroxytryptamine (5-HT, serotonin), dopamine and octopamine were investigated under either current-clamp or voltage-clamp conditions. The biogenic amines reversibly suppressed, but never totally abolished, ACh responses, 5-HT being the most potent, with a threshold near 10(-6) m (EC50 = 5 x 10(-5) M). Occlusion experiments indicate that the amines share a common mechanism at the level of either receptors or second messenger pathways, The amines also modulated responses to nicotine or carbachol (each of which resists hydrolysis by acetylcholinesterases), indicating that the amines did not act by accelerating ACh degradation. Pharmacological antagonists were used in an attempt to characterize the receptor responsible for amine-mediated modulation. Although a number of antagonists mimicked the action of amines rather than producing blockade, the antagonistic actions of LSD and RS23597 pointed strongly to a receptor-mediated mechanism, but did not allow receptor identification. The magnitude of the modulatory effect of 5-HT was significantly reduced by intracellular guanosine-5'-O-(2-thiodiphosphate) (GDP-beta-S), indicating involvement of a G-protein. Intracellular injection of the calcium chelator BAPTA did not block the modulatory effect of 5-HT, showing that the amines do not operate through the calcium-dependent pathway by which muscarinic receptors act on nicotinic currents. The adenylate cyclase inhibitor dideoxyadenosine (DDA), on the other hand, did attenuate the action of 5-HT, suggesting involvement of cyclic AMP.</p

Studies of cortical connectivity using optical circuit mapping methods

An important consideration when probing the function of any neuron is to uncover the source of synaptic input onto the cell, its intrinsic physiology and efferent targets. Over the years, electrophysiological approaches have generated considerable insight into these properties in a variety of cortical neuronal subtypes and circuits. However, as researchers explore neuronal function in greater detail, they are increasingly turning to optical techniques to bridge the gap between local network interactions and behaviour. The application of optical methods has increased dramatically over the past decade, spurred on by the optogenetic revolution. In this review, we provide an account of recent innovations, providing researchers with a primer detailing circuit mapping strategies in the cerebral cortex. We will focus on technical aspects of performing neurotransmitter uncaging and channelrhodopsin-assisted circuit mapping, with the aim of identifying common pitfalls that can negatively influence the collection of reliable data

Contribution of interneuron subtype-specific GABAergic signalling to emergent sensory processing in mouse somatosensory whisker barrel cortex

Mammalian neocortex is important for conscious processing of sensory information with balanced glutamatergic and GABAergic signaling fundamental to this function. Yet little is known about how this interaction arises despite increasing insight into early GABAergic interneuron (IN) circuits. To study this, we assessed the contribution of specific INs to the development of sensory processing in the mouse whisker barrel cortex, specifically the role of INs in early speed coding and sensory adaptation. In wild-type animals, both speed processing and adaptation were present as early as the layer 4 critical period of plasticity and showed refinement over the period leading to active whisking onset. To test the contribution of IN subtypes, we conditionally silenced action-potential-dependent GABA release in either somatostatin (SST) or vasoactive intestinal peptide (VIP) INs. These genetic manipulations influenced both spontaneous and sensory-evoked cortical activity in an age- and layer-dependent manner. Silencing SST + INs reduced early spontaneous activity and abolished facilitation in sensory adaptation observed in control pups. In contrast, VIP + IN silencing had an effect towards the onset of active whisking. Silencing either IN subtype had no effect on speed coding. Our results show that these IN subtypes contribute to early sensory processing over the first few postnatal weeks