Circuit contributions to sensory-driven glutamatergic drive of olfactory bulb mitral and tufted cells during odorant inhalation

In the mammalian olfactory bulb (OB), mitral/tufted (MT) cells respond to odorant inhalation with diverse temporal patterns that are thought to encode odor information. Much of this diversity is already apparent at the level of glutamatergic input to MT cells, which receive direct, monosynaptic excitatory input from olfactory sensory neurons (OSNs) as well as multisynaptic excitatory drive via glutamatergic interneurons. Both pathways are also subject to modulation by inhibitory circuits in the glomerular layer of the OB. To understand the role of direct OSN input versus postsynaptic OB circuit mechanisms in shaping diverse dynamics of glutamatergic drive to MT cells, we imaged glutamate signaling onto MT cell dendrites in anesthetized mice while blocking multisynaptic excitatory drive with ionotropic glutamate receptor antagonists and blocking presynaptic modulation of glutamate release from OSNs with GABAB receptor antagonists. GABAB receptor blockade increased the magnitude of inhalation-linked glutamate transients onto MT cell apical dendrites without altering their inhalation-linked dynamics, confirming that presynaptic inhibition impacts the gain of OSN inputs to the OB. Surprisingly, blockade of multisynaptic excitation only modestly impacted glutamatergic input to MT cells, causing a slight reduction in the amplitude of inhalation-linked glutamate transients in response to low odorant concentrations and no change in the dynamics of each transient. Postsynaptic blockade also modestly impacted glutamate dynamics over a slower timescale, mainly by reducing adaptation of the glutamate response across multiple inhalations of odorant. These results suggest that direct glutamatergic input from OSNs provides the bulk of excitatory drive to MT cells, and that diversity in the dynamics of this input may be a primary determinant of the temporal diversity in MT cell responses that underlies odor representations at this stage.

Temporal derivative computation in the dorsal raphe network revealed by an experimentally-driven augmented integrate-and-fire modeling framework

By means of an expansive innervation, the relatively few phylogenetically-old serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) are positioned to enact coordinated modulation of circuits distributed across the entire brain in order to adaptively regulate behavior. In turn, the activity of the DRN is driven by a broad set of excitatory inputs, yet the resulting network computations that naturally emerge from the excitability and connectivity features of the various cellular elements of the DRN are still unknown. To gain insight into these computations, we developed a flexible experimental and computational framework based on a combination of automatic characterization and network simulations of augmented generalized integrate-and-fire (aGIF) single-cell models. This approach enabled the examination of causal relationships between specific excitability features and identified population computations. We found that feedforward inhibition of 5-HT neurons by heterogeneous DRN somatostatin (SOM) neurons implemented divisive inhibition, while endocannabinoid-mediated modulation of excitatory drive to the DRN increased the gain of 5-HT output. The most striking computation that arose from this work was the ability of 5-HT output to linearly encode the derivative of the excitatory inputs to the DRN. This network computation primarily emerged from the prominent adaptation mechanisms found in 5-HT neurons, including a previously undescribed dynamic threshold. This novel computation in the DRN provides a potential mechanism underlying some of the functions recently ascribed to 5-HT in the context of reinforcement learning.

Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2-autoreceptor activity

SUMMARYThe nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show by application of several single-molecule sensitive super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the dopamine transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and by DA D2-autoreceptor activation in manner dependent on Ca2+-influx via N-type voltage-gated Ca2+-channels. The DAT nanodomains contain tens of transporters molecules and overlap with nanodomains of PIP2 (phosphatidylinositol-4,5-bisphosphate) but show little overlap with D2-autoreceptor, syntaxin-1 and clathrin nanodomains. By demonstrating that nanoscopic reorganizations with putative major impact on transmitter homeostasis can take place in dopaminergic varicosities, the data have important implications for understanding modulatory neurotransmitter physiology.

A direct excitatory action of lactate ions in the central respiratory network of bullfrogs, Lithobates catesbeianus

ABSTRACTChemoreceptors that detect O2 and CO2/pH regulate ventilation. However, recent work shows that lactate ions activate arterial chemoreceptors independent of pH to stimulate breathing. Although lactate rises in the central nervous system (CNS) during metabolic challenges, the ability of lactate ions to enhance ventilation by directly targeting the central respiratory network remains unclear. To address this possibility, we isolated the amphibian brainstem–spinal cord and found that small increases in CNS lactate stimulate motor output that causes breathing. In addition, lactate potentiated the excitatory postsynaptic strength of respiratory motor neurons, thereby coupling central lactate to the excitatory drive of neurons that trigger muscle contraction. Lactate did not affect motor output through pH or pyruvate metabolism, arguing for sensitivity to lactate anions per se. In sum, these results introduce a mechanism whereby lactate ions in the CNS match respiratory motor output to metabolic demands.

Role of High Frequency Oscillations of Somatosensory Evoked Potentials in Deciphering Pathophysiology of Migraine

Background Habituation deficit is considered as a neurophysiological abnormality among migraineurs in the interictal period. For clear comprehension and clarity about the mechanism underlying habituation in migraine, a sophisticated method, i.e., high frequency oscillations (HFOs) evoked potentials, have been utilized. However, studies pertaining to this in the Indian context are rare. Objective The aim of the study is to determine the utility of HFO of somatosensory evoked potential (SSEP) in deciphering the pathophysiology of migraine. Materials and Methods Sixty subjects including 30 migraineurs in the interictal period and 30 healthy controls were considered for the study. Median nerve SSEP was recorded in patients and controls by standard protocols. HFO was extracted offline using the Digital zero-phase shift band-pass filtering at 450 and 750 Hz. The early and late HFOs were determined with respect to the N20 peak and were compared between the groups. Results Of total 30 migraineurs, 18 had hemicranial headache and 12 had holocranial headache. N20 latency, P25 latency, N20 onset to peak amplitude, and N20 onset to P25 amplitude were comparable in migraineurs and controls. The intraburst frequency of early HFOs in migraineurs was significantly higher (p = 0.04), whereas the peak-to-peak amplitude was significantly lower (p = 0.001). Conclusion Early HFOs on SSEP represent the thalamocortical excitatory drive in migraineurs. Overall, the study reports that reduced amplitude of early HFOs in the interictal period suggest reduced thalamocortical drive in migraineurs.

Multi-Level Regulation of Opioid-Induced Respiratory Depression

Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBötzinger Complex as well as from depression of the Parabrachial/Kölliker-Fuse Complex, which provides excitatory drive to preBötzinger Complex neurons mediating respiratory phase-switch. Opioids also depress awake drive from the forebrain and chemodrive.