In the primary motor cortex (M1), layer 5 projection neurons signal directly to distant motor structures to drive movement. Despite their pivotal position and acknowledged diversity these neurons are traditionally separated into broad commissural and corticofugal types, and until now no attempt has been made at resolving the basis for their diversity. We therefore probed the electrophysiological and morphological properties of retrogradely labeled M1 corticospinal (CSp), corticothalamic (CTh), and commissural projecting corticostriatal (CStr) and corticocortical (CC) neurons. An unsupervised cluster analysis established at least four phenotypes with additional differences between lumbar and cervical projecting CSp neurons. Distinguishing parameters included the action potential (AP) waveform, firing behavior, the hyperpolarisation-activated sag potential, sublayer position, and soma and dendrite size. CTh neurons differed from CSp neurons in showing spike frequency acceleration and a greater sag potential. CStr neurons had the lowest AP amplitude and maximum rise rate of all neurons. Temperature influenced spike train behavior in corticofugal neurons. At 26°C CTh neurons fired bursts of APs more often than CSp neurons, but at 36°C both groups fired regular APs. Our findings provide reliable phenotypic fingerprints to identify distinct M1 projection neuron classes as a tool to understand their unique contributions to motor function.

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The design and preparation of synthetic binders (SBs) applicable for small biomolecule sensing in aqueous media remains very challenging. SBs designed by the lock‐and‐key principle can be selective for their target analyte but usually show an insufficient binding strength in water. In contrast, SBs based on symmetric macrocycles with a hydrophobic cavity can display high binding affinities but generally suffer from indiscriminate binding of many analytes. Herein, a completely new and modular receptor design strategy based on microporous hybrid materials is presented yielding zeolite‐based artificial receptors (ZARs) which reversibly bind the neurotransmitters serotonin and dopamine with unprecedented affinity and selectivity even in saline biofluids. ZARs are thought to uniquely exploit both the non‐classical hydrophobic effect and direct non‐covalent recognition motifs, which is supported by in‐depth photophysical, and calorimetric experiments combined with full atomistic modeling. ZARs are thermally and chemically robust and can be readily prepared at gram scales. Their applicability for the label‐free monitoring of important enzymatic reactions, for (two‐photon) fluorescence imaging, and for high‐throughput diagnostics in biofluids is demonstrated. This study showcases that artificial receptor based on microporous hybrid materials can overcome standing limitations of synthetic chemosensors, paving the way towards personalized diagnostics and metabolomics.

Detection of Neurotransmitters So far, only modestly performing synthetic binders have been accessible for small bioactive molecules such as serotonin and dopamine. In article number 2104614, Luisa De Cola, Frank Biedermann, and co‐workers introduce zeolite‐based artificial receptors (ZARs), which are microporous inorganic–organic hybrid materials applicable for the optical‐based detection of serotonin and dopamine in urine at physiological relevant concentrations. These ZARs outperform protein receptors with respect to response times, robustness and scalability.