Centrifugal projections in the olfactory system are critical to both olfactory processing and behavior. The olfactory bulb (OB), the first relay station in odor processing, receives a substantial number of centrifugal inputs from the central brain regions. However, the anatomical organization of these centrifugal connections has not been fully elucidated, especially for the excitatory projection neurons of the OB, the mitral/tufted cells (M/TCs). Using rabies virus-mediated retrograde monosynaptic tracing in Thy1-Cre mice, we identified that the three most prominent inputs of the M/TCs came from the anterior olfactory nucleus (AON), the piriform cortex (PC), and the basal forebrain (BF), similar to the granule cells (GCs), the most abundant population of inhibitory interneurons in the OB. However, M/TCs received proportionally less input from the primary olfactory cortical areas, including the AON and PC, but more input from the BF and contralateral brain regions than GCs. Unlike organizationally distinct inputs from the primary olfactory cortical areas to these two types of OB neurons, inputs from the BF were organized similarly. Furthermore, individual BF cholinergic neurons innervated multiple layers of the OB, forming synapses on both M/TCs and GCs. Taken together, our results indicate that the centrifugal projections to different types of OB neurons may provide complementary and coordinated strategies in olfactory processing and behavior.

Background: Drug‐resistant epilepsy (DRE) affects nearly one‐third of patients and remains a major unmet clinical need, despite advances in anti‐seizure medications (ASMs). Carbogen, a low‐concentration carbon dioxide (CO ₂ ) and oxygen (O ₂ ) gas mixture, has reemerged as a physiology‐based therapy owing to renewed insights into pH‐sensitive seizure mechanisms. Methods: This review summarizes preclinical and clinical evidence on carbogen inhalation for seizure control. Mechanistic data on pH‐dependent ion channels, GABAergic inhibition, and adenosine signaling were condensed, and clinical outcomes across seizure types and inhalation protocols were compared for safety and efficacy. Results: Carbogen induces short‐term respiratory acidosis, lowering brain extracellular pH to activate acid‐sensitive ion channels (e.g., ASIC1a and NaV1.2), enhance GABAergic inhibition, and boost adenosine signaling. These effects are rapid, reversible, and distinct from conventional ASMs. Preclinical studies show strong seizure suppression, especially under hyperventilation‐induced alkalosis. Clinically, brief low‐dose inhalation (5% CO ₂ for ≤ 3 min) is effective and well tolerated in focal and absence seizures, whereas earlier high‐concentration protocols caused adverse effects. Efficacy varies by seizure type: benefits in nonconvulsive status epilepticus (NCSE) are limited, and the CARDIF trial found no advantage for pediatric febrile seizures. Ongoing work, such as the CRESCENT trial, is exploring carbogen as an adjunct therapy for pediatric convulsive status epilepticus (CSE). Conclusions: Evidence supports carbogen's therapeutic promise and highlights the need for precise patient selection, controlled delivery, and comprehensive safety testing. Future research should develop biomarker‐guided, closed‐loop systems and test synergy with established ASMs to advance carbogen as a mechanism‐based therapy within precision epilepsy care.

Optogenetic manipulation is pivotal in basic neuroscience research and in studying neuropsychiatric disorders, enabling the activation or inhibition of neuronal populations with millisecond precision. However, this technique can induce artificial neuronal hypersynchronization that is rarely observed under physiological conditions. Given that epileptic seizures arise from abnormally synchronized neuronal discharges, the potential for optogenetic stimulation to trigger seizures and confound experimental outcomes warrants close examination. Here, using electrophysiological and behavioral recordings, we demonstrate that even single-trial optogenetic stimulation of CaMKII-positive neurons in the hippocampal CA1 region, anterior piriform cortex (APC), or lateral/medial entorhinal cortex (LEnt or MEnt) can induce seizure-like discharges and behaviors in adult male C57BL/6 mice. Repeated stimulation in the APC, LEnt, or MEnt elicited more severe seizure-like activity. Furthermore, stimulation protocols characterized by high power, long duration, high frequency, and medium pulse width were more prone to inducing such events. Additionally, we found that CA1 stimulation could impair subsequent contextual fear memory. These findings provide critical cautions and practical guidelines for the design and implementation of in vivo optogenetic experiments in neuroscience research.