Hibernation reduces GABA signaling in the brainstem to enhance motor activity of breathing at cool temperatures.

Background: Neural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations.

Age-related increase in the excitability of mouse layer V pyramidal neurons in the primary motor cortex is accompanied by an increased persistent inward current.

Sarcopenia, or pathological age-related loss of muscle strength and mass, contributes to physical function impairment in older adults. While current understanding of sarcopenia is centered mostly on neuromuscular mechanisms, mounting evidence supports that deficits at the level of the primary motor cortex (PMC) play a significant role. Despite the importance of the PMC to initiate movement, understanding of how age affects the excitability of layer V pyramidal neurons (LVPNs) of the PMC is limited.

Hibernation reduces GABA signaling in the brainstem to enhance motor activity of breathing at cool temperatures.

Background: Neural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations.

Activation of respiratory-related bursting in an isolated medullary section from adult bullfrogs.

Breathing is generated by a rhythmic neural circuit in the brainstem, which contains conserved elements across vertebrate groups. In adult frogs, the 'lung area' located in the reticularis parvocellularis is thought to represent the core rhythm generator for breathing. Although this region is necessary for breathing-related motor output, whether it functions as an endogenous oscillator when isolated from other brainstem centers is not clear.

Molecular profiling of CO/pH-sensitive neurons in the locus coeruleus of bullfrogs reveals overlapping noradrenergic and glutamatergic cell identity.

Locus coeruleus (LC) neurons regulate breathing by sensing CO/pH. Neurons within the vertebrate LC are the main source of norepinephrine within the brain. However, they also use glutamate and GABA for fast neurotransmission.

Series resistance errors in whole cell voltage clamp measured directly with dual patch-clamp recordings: not as bad as you think.

Whole cell patch clamp has provided much insight into the function of voltage-gated ion channels in central neurons. However, voltage errors caused by the resistance of the recording electrode [series resistance ()] limit its application to relatively small ionic currents. Ohm's law is often applied to estimate and correct the membrane potential for these voltage errors.

Synaptic modifications transform neural networks to function without oxygen.

Background: Neural circuit function is highly sensitive to energetic limitations. Much like mammals, brain activity in American bullfrogs quickly fails in hypoxia. However, after emergence from overwintering, circuits transform to function for approximately 30-fold longer without oxygen using only anaerobic glycolysis for fuel, a unique trait among vertebrates considering the high cost of network activity.

Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress.

Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia.

Neuron populations use variable combinations of short-term feedback mechanisms to stabilize firing rate.

Neurons tightly regulate firing rate and a failure to do so leads to multiple neurological disorders. Therefore, a fundamental question in neuroscience is how neurons produce reliable activity patterns for decades to generate behavior. Neurons have built-in feedback mechanisms that allow them to monitor their output and rapidly stabilize firing rate.

Transformation to ischaemia tolerance of frog brain function corresponds to dynamic changes in mRNA co-expression across metabolic pathways.

Neural activity is costly and requires continuous ATP from aerobic metabolism. Brainstem motor function of American bullfrogs normally collapses after minutes of ischaemia, but following hibernation, it becomes ischaemia-tolerant, generating output for up to 2 h without oxygen or glucose delivery. Transforming the brainstem to function during ischaemia involves a switch to anaerobic glycolysis and brain glycogen.

Inactivity and Ca signaling regulate synaptic compensation in motoneurons following hibernation in American bullfrogs.

Neural networks tune synaptic and cellular properties to produce stable activity. One form of homeostatic regulation involves scaling the strength of synapses up or down in a global and multiplicative manner to oppose activity disturbances. In American bullfrogs, excitatory synapses scale up to regulate breathing motor function after inactivity in hibernation, connecting homeostatic compensation to motor behavior.

A brainstem preparation allowing simultaneous access to respiratory motor output and cellular properties of motoneurons in American bullfrogs.

Breathing is generated by a complex neural circuit, and the ability to monitor the activity of multiple network components simultaneously is required to uncover the cellular basis of breathing. In neonatal rodents, a single brainstem slice can be obtained to record respiratory-related motor nerve discharge along with individual rhythm-generating cells or motoneurons because of the close proximity of these neurons in the brainstem. However, most ex vivo preparations in other vertebrates can only capture respiratory motor outflow or electrophysiological properties of putative respiratory neurons in slices without relevant synaptic inputs.

Transforming a neural circuit to function without oxygen and glucose delivery.

Disruptions in the delivery of oxygen and glucose impair the function of neural circuits, with lethal consequences commonly observed in stroke and cardiac arrest. Intense focus has been placed on understanding how to overcome neuronal failure during energy stress. Important insights into neuroprotective strategies have come from studies of evolutionary adaptations for survival in hypoxic environments, such as those seen in turtles, naked mole-rats, and several other animals.

Lactate ions induce synaptic plasticity to enhance output from the central respiratory network.

Lactate ion sensing has emerged as a process that regulates ventilation during metabolic challenges. Most work has focused on peripheral sensing of lactate for the control of breathing. However, lactate also rises in the central nervous system (CNS) during disturbances to blood gas homeostasis and exercise.

Characterization of laryngeal motor neuron properties in the American bullfrog, Lithobates catesbieanus.

Motor neurons represent the final output from the central respiratory network. American bullfrogs, Lithobates catesbieanus, have provided insight into development and plasticity of the breathing control system, yet cellular aspects of bullfrog motor neurons are not well-described. In this study, we characterized properties of laryngeal motor neurons that produce motor outflow to the glottal dilator, a muscle that gates airflow to the lungs of anurans.

Neuromodulation or energy failure? Metabolic limitations silence network output in the hypoxic amphibian brainstem.

Hypoxia tolerance in the vertebrate brain often involves chemical modulators that arrest neuronal activity to conserve energy. However, in intact networks, it can be difficult to determine whether hypoxia triggers modulators to stop activity in a protective manner or whether activity stops because rates of ATP synthesis are insufficient to support network function. Here, we assessed the extent to which neuromodulation or metabolic limitations arrest activity in the respiratory network of bullfrogs-a circuit that survives moderate periods of oxygen deprivation, presumably, by activating an inhibitory noradrenergic pathway.

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

Chemoreceptors that detect O and CO/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.

Molecular profiling of single neurons of known identity in two ganglia from the crab .

Understanding circuit organization depends on identification of cell types. Recent advances in transcriptional profiling methods have enabled classification of cell types by their gene expression. While exceptionally powerful and high throughput, the ground-truth validation of these methods is difficult: If cell type is unknown, how does one assess whether a given analysis accurately captures neuronal identity? To shed light on the capabilities and limitations of solely using transcriptional profiling for cell-type classification, we performed 2 forms of transcriptional profiling-RNA-seq and quantitative RT-PCR, in single, unambiguously identified neurons from 2 small crustacean neuronal networks: The stomatogastric and cardiac ganglia.

Motor inactivity in hibernating frogs: Linking plasticity that stabilizes neuronal function to behavior in the natural environment.

All animals must generate reliable neuronal activity to produce adaptive behaviors in an ever-changing environment. Neural systems are thought to achieve this goal, in part, through cellular and synaptic plasticity mechanisms that stabilize electrophysiological functions. Despite strong evidence for a role in regulating neuronal properties, these plasticity mechanisms have been difficult to link to natural behaviors in animals.

The differential contribution of pacemaker neurons to synaptic transmission in the pyloric network of the Jonah crab, .

Many neurons receive synchronous input from heterogeneous presynaptic neurons with distinct properties. An instructive example is the crustacean stomatogastric pyloric circuit pacemaker group, consisting of the anterior burster (AB) and pyloric dilator (PD) neurons, which are active synchronously and exert a combined synaptic action on most pyloric follower neurons. Previous studies in lobster have indicated that AB is glutamatergic, whereas PD is cholinergic.

Membrane Voltage Is a Direct Feedback Signal That Influences Correlated Ion Channel Expression in Neurons.

The number and type of ion channels present in the membrane determines the electrophysiological function of every neuron. In many species, stereotyped output of neurons often persists for years [1], and ion channel dysregulation can change these properties to cause severe neurological disorders [2-4]. Thus, a fundamental question is how do neurons coordinate channel expression to uphold their firing patterns over long timescales [1, 5]? One major hypothesis purports that neurons homeostatically regulate their ongoing activity through mechanisms that link membrane voltage to expression relationships among ion channels [6-10].

High Fat Feeding in Rats Alters Respiratory Parameters by a Mechanism That Is Unlikely to Be Mediated by Carotid Body Type I Cells.

The carotid bodies (CB) respond to changes in blood gases with neurotransmitter release, thereby increasing carotid sinus nerve firing frequency and ultimately correcting the pattern of breathing. It has previously been demonstrated that acute application of the adipokine leptin augments the hypoxic sensory response of the intact in-vitro CB (Pye RL, Roy A, Wilson RJ, Wyatt CN. FASEB J 30(1 Supplement):983.

Noradrenergic modulation determines respiratory network activity during temperature changes in the in vitro brainstem of bullfrogs.

Among vertebrate ectotherms, air breathing frequency is generally constrained across warmer temperatures, but decreases during cooling. The brainstem mechanisms that give rise to this ventilatory strategy are unclear. Neuromodulation has recently been shown to stabilize motor circuit output across temperatures.

Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats.

Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex).