Changes In Firing Rate Of Neurons Research Articles

Amyloid Precursor Protein Can Cause Changes in Neuronal Firing Rates via Axon Initial Segment.

Amyloid Precursor Protein Can Cause Changes in Neuronal Firing Rates via Axon Initial Segment.

Systems-level analysis of local field potentials reveals differential effects of lysergic acid diethylamide and ketamine on neuronal activity and functional connectivity.

Psychedelic substances have in recent years attracted considerable interest as potential treatments for several psychiatric conditions, including depression, anxiety, and addiction. Imaging studies in humans point to a number of possible mechanisms underlying the acute effects of psychedelics, including changes in neuronal firing rates and excitability as well as alterations in functional connectivity between various brain nodes. In addition, animal studies using invasive recordings, have suggested synchronous high-frequency oscillations involving several brain regions as another key feature of the psychedelic brain state. To better understand how the imaging data might be related to high-resolution electrophysiological measurements, we have here analyzed the aperiodic part of the local field potential (LFP) in rodents treated with a classic psychedelic (LSD) or a dissociative anesthetic (ketamine). In addition, functional connectivity, as quantified by mutual information measures in the LFP time series, has been assessed with in and between different structures. Our data suggest that the altered brain states of LSD and ketamine are caused by different underlying mechanisms, where LFP power shifts indicate increased neuronal activity but reduced connectivity following ketamine, while LSD also leads to reduced connectivity but without an accompanying change in LFP broadband power.

Decoding human spontaneous spiking activity in medial temporal lobe from scalp EEG

Linking scalp electroencephalography (EEG) signals and spontaneous firing activity from deep nuclei in humans is not trivial. To examine this, we analyzed simultaneous recordings of scalp EEG and unit activity in deeply located sites recorded overnight from patients undergoing pre-surgical invasive monitoring. We focused on modeling the within-subject average unit activity of two medial temporal lobe areas: amygdala and hippocampus. Linear regression model correlates the units' average firing activity to spectral features extracted from the EEG during wakefulness or non-REM sleep. We show that changes in mean firing activity in both areas and states can be estimated from EEG (Pearson r>0.2, p≪0.001). Region specificity was shown with respect to other areas. Both short- and long-term fluctuations in firing rates contributed to the model accuracy. This demonstrates that scalp EEG frequency modulations can predict changes in neuronal firing rates, opening a new horizon for non-invasive neurological and psychiatric interventions.

Treatments to Combat Opiate Dependence

The current opioid epidemic is a pressing public health concern that has been difficult to address because there is no generally accepted hypothesis to explain the underlying neurophysiological mechanism(s) that lead to tolerance and withdrawal, which in turn could serve as the basis for developing therapeutic interventions. As a step to developing such a unifying mechanistic hypothesis we studied both the electrophysiological firing patterns of individual neurons and behaviors indicative of tolerance and withdrawal in rats following chronic administration of morphine. Neuronal activity recordings from the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), thalamus, hypothalamus, hippocampus (HIPP), Amygdala (AMYG) and caudate nucleus (CN) following exposure of repetitive (chronic) morphine produced a new baseline pattern of neuronal firing rates, which we refer to as an “opioid-induced pattern” in the mesocorticolimbic neuronal activity circuit, which is thought to be involved in mediating the “reward” effects of opioid and other drugs of abuse. These changes in neuronal firing rate was paralleled by behavioral changes indicative of the development of dependence such as tolerance and withdrawal suggesting a possible cause-effect relationship between the opioid induced pattern change of baseline neuronal firing and the development of opioid tolerance and withdrawal. Briefly, (i) morphine produces a new baseline pattern of neuronal firing (i.e., an “opioid-induced pattern”), (ii) there is an intrinsic neurophysiological mechanism that seeks to maintain newly established patterns of baseline neuronal firing once established, (iii) continued morphine administration maintains the new pattern of baseline neuronal activity so that withdrawal behaviors do not occur, but (iv) eventual discontinuation of the drug leads to opioid withdrawal symptoms. Consistent with this proposed hypothesis, co-administration of the immunomodulator such as interferon, cyclosporin and cortisol attenuated both the development of an altered baseline pattern of neuronal firing and the parallel behavioral changes. This observation suggests that immunomodifiers treatment to morphine dependence subject restore the neuronal firing rate to its pre-morphine baseline and thus alleviate the withdrawal symptoms that make is so difficult for addicts to discontinue opioid use. The studies in this review describe in more detail the findings that led to our proposed hypothesis for the underlying neurophysiological basis of the development of opioid tolerance and withdrawal and the possible use of immunomodulators to decrease the development of dependence and thereby attenuate withdrawal symptoms that make it so difficult for addicts to discontinue drug use. Repetitive use of opioids results in dependence on the drug, a complex condition that is considered to be an opiate use disorder (OUD). The reduction or cessation of opioid consumption leads to severe withdrawal behaviors. The degree of opiate dependence can be assessed by the intensity of the withdrawal behavior. To prevent this devastating opiate withdrawal syndrome, the subject will continue to take the drug. Success in modifying the withdrawal behavior may shed light on the dynamics of OUD and help to curb the opiate epidemic. Classical therapeutic addiction research has focused on cellular and molecular alterations within neurons and their neuronal circuits. As such, most of the pharmacotherapies for opioid addiction are designed to target the neuronal processes known to be affected by drug intake. In addition to the pivotal role of neurons in the initiation, transition, and maintenance of opioid dependence, the glial cells within the central nervous system are also of particular importance. According to some studies, 60 to 80% of the cellular brain is composed of glial cells. Recent studies have shown that glial cells participate in synaptogenesis, neuronal excitability, and neurotransmission. Following opioid exposure, glial cells demonstrate robust changes in their morphology and physiology in key central nervous system regions known to contribute to drug dependence. They play a pivotal role in opioid-addiction like behaviors. Glial cells are also part of the immune system. This review summarizes studies demonstrating that the immune system participates in the expression of opiate withdrawal and that a single dose of immunological substances such as α-interferon, cyclosporine, or cortisol significantly attenuates the severity of the naloxone-induced withdrawal symptoms in opioid-dependent animals. These preclinical studies provide a new approach to treat opiate dependence using immunomodulators that do not belong to the opiate family. We hope that this review will encourage translational studies to use immunomodulators in combating the opioid epidemic and save lives.

Toxic effect of calcium/calmodulin kinase II on anxiety behavior, neuronal firing and plasticity in the male offspring of morphine-abstinent rats

Studies have shown that epigenetic changes such as alteration in histone acetylation and DNA methylation in various brain regions play an essential role in anxiety behavior. According to the critical role of calcium/calmodulin protein kinaseII (CaMKII) in these processes, the present study examined the effect of CaMKII inhibitor (KN93) on neuronal activity and level of c-fos in the amygdala and nucleus accumbens (NAC) in the offspring of morphine-exposed parents.Adult male and female Wistar rats received morphine orally (for 21 days). After the washout period (10 days), rats were mated with either drug-naïve or morphine-exposed rats. KN93 was microinjected into the brain of male offspring. The anxiety-like behavior, the neuronal firing rate in the NAC and the amygdala and level of c-fos were assessed by related techniques.Data showed the offspring with one and/or two morphine-abstinent parent(s) had more anxiety-like behavior than the control group. However, the administration of KN-93 decreased anxiety in the offspring of morphine-exposed rats compared with saline-treated groups. The expression level of the c-fos was not significantly altered by the inhibition of CaMKII in the amygdala, but the c-fos level was reduced in the NAC. The neuronal firing rate of these groups was associated with an increase in the amygdala in comparison to the saline groups but was decreased in the NAC.Results showed that CaMKII had a role in anxiety-like behavior in the offspring of morphine-exposed parents, and changes in neuronal firing rate and c-fos level in the NAC might be involved in this process.

Changes in Local Network Activity Approximated by Reverse Spike-Triggered Local Field Potentials Predict the Focus of Attention.

The effects of visual spatial attention on neuronal firing rates have been well characterized for neurons throughout the visual processing hierarchy. Interestingly, the mechanisms by which attention generates more or fewer spikes in response to a visual stimulus remain unknown. One possibility is that attention boosts the likelihood that synaptic inputs to a neuron result in spikes. We performed a novel analysis to measure local field potentials (LFPs) just prior to spikes, or reverse spike-triggered LFP “wavelets,” for neurons recorded in primary visual cortex (V1) of monkeys performing a contrast change detection task requiring covert shifts in visual spatial attention. We used dimensionality reduction to define LFP wavelet shapes with single numerical values, and we found that LFP wavelet shape changes correlated with changes in neuronal firing rate. We then tested whether a simple classifier could predict monkeys’ focus of attention from LFP wavelet shape. LFP wavelet shapes sampled in discrete windows were predictive of the locus of attention for some neuronal types. These findings suggest that LFP wavelets are a useful proxy for local network activity influencing spike generation, and changes in LFP wavelet shape are predictive of the focus of attention.

Modulation of Functional Connectivity Between Dopamine Neurons of the Rat Ventral Tegmental Area in vitro.

Micro Electrode Arrays were used to simultaneously record spontaneous extracellular action potentials from 10 to 30 dopamine neurons in acute brain slices from the lateral Ventral Tegmental Area (VTA) of the rat. The spike train of an individual neuron was used to characterize the firing pattern: firing rate, firing irregularity and oscillation frequency. Functional connectivity between a pair of neurons was quantified by the Paired Phase Consistency (PPC), taking the oscillation frequency as reference. Under baseline conditions the PPC was significantly different from zero and 42 of the 386 pairs of VTA neurons showed significant coupling. Fifty percent of the recorded dopamine neurons were part of the coupled VTA network. Raising extracellular potassium from 3.5 to 5 mM increased the mean firing rate of the dopamine neurons by 45%. The same increase could be induced by bath application of 300 μm glutamate. High potassium reduced the PPC, but it did not change during the glutamate application. Our findings imply that manipulating excitability has distinct and specific consequences for functional connectivity in the VTA network that cannot be directly predicted from the changes in neuronal firing rates. Functional connectivity reflects the spatial organization and synchronization of the VTA output and thus represents a unique element of the message that is sent to the mesolimbic projection area. It adds a dimension to pharmacological manipulation of the VTA micro circuit that might help to understand the pharmacological (side) effects of e.g., anti-psychotic drugs.

Chapter 22 - Electrophysiologic mapping for deep brain stimulation for movement disorders

Electrophysiologic mapping remains an integral component of deep brain stimulation (DBS) surgical procedures, particularly in movement disorder cases where functional maps are used to guide DBS lead placement in patients with Parkinson's disease, dystonia, or tremor. Overall, the goal of the surgical procedure is to implant the distal end of a chronic, multicontact depth electrode into a specific brain region for the purpose of delivering therapeutic electrical stimulation. Regions that are currently targeted for patients with movement disorders include the subthalamic nucleus, the ventral intermediate nucleus of the thalamus, and the globus pallidus. Multiple imaging modalities are used initially to derive a stereotactic plan and guide the initial microelectrode trajectory. Changes in neuronal firing rate and pattern, both spontaneous and in response to somatosensory stimulation, are used to establish the location of the tip of the microelectrode(s), while acute stimulation can be used to estimate the proximity of neighboring brain regions. In this chapter, we will provide an overview of the microelectrode recording process as it is commonly applied to refine image-based targeting of lead placement for DBS surgery.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement.

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN.

Reduced reach-related modulation of motor thalamus neural activity in a rat model of Parkinson's disease.

Motor thalamus (Mthal) is a key node in the corticobasal ganglia (BG) loop that controls complex, cognitive aspects of movement. In Parkinson's disease (PD), profound alterations in neuronal activity occur in BG nuclei and cortex. Because Mthal is located between these two structures, altered Mthal activity has been assumed to underlie the pathogenesis of PD motor deficits. However, to date, inconsistent changes in neuronal firing rate and pattern have been reported in parkinsonian animals. Moreover, although a distinct firing pattern of Mthal neurons, called low-threshold calcium spike bursts (LTS bursts), is observed in reduced preparations, it remains unknown whether they occur or what their role might be in behaving animals. We recorded Mthal spiking activity in control and unilateral 6-hydroxydopamine lesioned rats performing a skilled forelimb-reaching task. We show for the first time that Mthal firing rate in control rats is modulated in a temporally precise pattern during reach-to-grasp movements, with a peak at the time of the reach-end and troughs just before and after it. We identified LTS-like events on the basis of LTS burst characteristics. These were rare, but also modulated, decreasing in incidence just after reach-end. The inhibitory modulations in firing rate and LTS-like events were abolished in parkinsonian rats. These data confirm that nigrostriatal dopamine depletion is accompanied by profound and specific deficits in movement-related Mthal activity. These changes would severely impair Mthal contributions to motor program development in motor cortex and are likely to be an important factor underlying the movement deficits of PD.

Emergent selectivity for task-relevant stimuli in higher-order auditory cortex.

A variety of attention-related effects have been demonstrated in primary auditory cortex (A1). However, an understanding of the functional role of higher auditory cortical areas in guiding attention to acoustic stimuli has been elusive. We recorded from neurons in two tonotopic cortical belt areas in the dorsal posterior ectosylvian gyrus (dPEG) of ferrets trained on a simple auditory discrimination task. Neurons in dPEG showed similar basic auditory tuning properties to A1, but during behavior we observed marked differences between these areas. In the belt areas, changes in neuronal firing rate and response dynamics greatly enhanced responses to target stimuli relative to distractors, allowing for greater attentional selection during active listening. Consistent with existing anatomical evidence, the pattern of sensory tuning and behavioral modulation in auditory belt cortex links the spectrotemporal representation of the whole acoustic scene in A1 to a more abstracted representation of task-relevant stimuli observed in frontal cortex.

Bidirectional Scaling of Astrocytic Metabotropic Glutamate Receptor Signaling following Long-Term Changes in Neuronal Firing Rates

Very little is known about the ability of astrocytic receptors to exhibit plasticity as a result of changes in neuronal activity. Here we provide evidence for bidirectional scaling of astrocytic group I metabotropic glutamate receptor signaling in acute mouse hippocampal slices following long-term changes in neuronal firing rates. Plasticity of astrocytic mGluRs was measured by recording spontaneous and evoked Ca2+ elevations in both astrocytic somata and processes. An exogenous astrocytic Gq G protein-coupled receptor was resistant to scaling, suggesting that the alterations in astrocyte Ca2+ signaling result from changes in activity of the surface mGluRs rather than a change in intracellular G protein signaling molecules. These findings suggest that astrocytes actively detect shifts in neuronal firing rates and adjust their receptor signaling accordingly. This type of long-term plasticity in astrocytes resembles neuronal homeostatic plasticity and might be important to ensure an optimal or expected level of input from neurons.

Changes in neuronal firing rate in the subthalamic nucleus with Parkinson's disease

Changes in neuronal firing rate in the subthalamic nucleus with Parkinson's disease

Motor Planning under Unpredictable Reward: Modulations of Movement Vigor and Primate Striatum Activity

Although reward probability is an important factor that shapes animal's behavior, it is not well understood how the brain translates reward expectation into the vigor of movement [reaction time (RT) and speed]. To address this question, we trained two monkeys in a RT task that required wrist movements in response to vibrotactile and visual stimuli, with a variable reward schedule. Correct performance was rewarded in 75% of the trials. Monkeys were certain that they would be rewarded only in the trials immediately following withheld rewards. In these trials, the animals responded sooner and moved faster. Single-unit recordings from the dorsal striatum revealed modulations in neural firing that reflected changes in movement vigor. First, in the trials with certain rewards, striatal neurons modulated their firing rates earlier. Second, magnitudes of changes in neuronal firing rates depended on whether or not monkeys were certain about the reward. Third, these modulations depended on the sensory modality of the cue (visual vs. vibratory) and/or movement direction (flexions vs. extensions). We conclude that dorsal striatum may be a part of the mechanism responsible for the modulation of movement vigor in response to changes of reward predictability.

Modulation of neuronal activity and plasma membrane properties with low-power millimeter waves in organotypic cortical slices

As millimeter waves (MMWs) are being increasingly used in communications and military applications, their potential effects on biological tissue has become an important issue for scientific inquiry. Specifically, several MMW effects on the whole-nerve activity were reported, but the underlying neuronal changes remain unexplored. This study used slices of cortical tissue to evaluate the MMW effects on individual pyramidal neurons under conditions mimicking their in vivo environment. The applied levels of MMW power are three orders of magnitude below the existing safe limit for human exposure of 1 mW cm−2. Surprisingly, even at these low power levels, MMWs were able to produce considerable changes in neuronal firing rate and plasma membrane properties. At the power density approaching 1 µW cm−2, 1 min of MMW exposure reduced the firing rate to one third of the pre-exposure level in four out of eight examined neurons. The width of the action potentials was narrowed by MMW exposure to 17% of the baseline value and the membrane input resistance decreased to 54% of the baseline value across all neurons. These effects were short lasting (2 min or less) and were accompanied by MMW-induced heating of the bath solution at 3 °C. Comparison of these results with previously published data on the effects of general bath heating of 10 °C indicated that MMW-induced effects cannot be fully attributed to heating and may involve specific MMW absorption by the tissue. Blocking of the intracellular Ca2+-mediated signaling did not significantly alter the MMW-induced neuronal responses suggesting that MMWs interacted directly with the neuronal plasma membrane. The presented results constitute the first demonstration of direct real-time monitoring of the impact of MMWs on nervous tissue at a microscopic scale. Implication of these findings for the therapeutic modulation of neuronal excitability is discussed.

Deep Brain Stimulation Reduces Neuronal Entropy in the MPTP-Primate Model of Parkinson's Disease

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) or internal segment of the globus pallidus is a clinically successful treatment for the motor symptoms of Parkinson's disease. However, the mechanisms by which HFS alleviates these symptoms are not understood. Whereas initial studies focused on HFS-induced changes in neuronal firing rates, recent studies suggest that changes in patterns of neuronal activity may correlate with symptom alleviation. We hypothesized that effective STN HFS reduces the disorder of neuronal firing patterns in the basal ganglia thalamic circuit, minimizing the pathological activity associated with parkinsonism. Stimulating leads were implanted in the STN of two rhesus monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Action potentials were recorded from neurons of the internal and external globus pallidus and the motor thalamus (ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis) during HFS that reduced motor symptoms and during clinically ineffective low-frequency stimulation (LFS). Firing pattern entropy was calculated from the recorded spike times to quantify the disorder of the neuronal activity. The firing pattern entropy of neurons within each region of the pallidum and motor thalamus decreased in response to HFS (n > or = 18 and P < or = 0.02 in each region), whereas firing rate changes were specific to pallidal neurons only. In response to LFS, firing rates were unchanged, but firing pattern entropy increased throughout the circuit (n > or = 24 and P < or = 10(-4) in each region). These data suggest that the clinical effectiveness of HFS is correlated with, and potentially mediated by, a regularization of the pattern of neuronal activity throughout the basal ganglia thalamic circuit.

Out of synch: Clock mutation causes obesity in mice

The Clock gene encodes an essential component of the "master clock" driving circadian rhythm in the hypothalamic suprachiasmatic nucleus (SCN). New evidence that Clock mutant mice are hyperphagic and obese suggests a previously unrecognized link between molecular controls of circadian rhythm and energy homeostasis.

Robust persistent neural activity in a model integrator with multiple hysteretic dendrites per neuron.

Short-term memory is often correlated with persistent changes in neuronal firing rates in response to transient inputs. We model the persistent maintenance of an analog eye position signal by an oculomotor neural integrator receiving transient eye movement commands. Previous models of this network rely on precisely tuned positive feedback with <1% tolerance to mistuning, or use neurons that exhibit large discontinuities in firing rate with small changes in eye position. We show analytically how using neurons with multiple bistable dendritic compartments can enhance the robustness of eye fixations to mistuning while reproducing the approximately linear and continuous relationship between neuronal firing rates and eye position, and the dependence of neuron pair firing rate relationships on the direction of the previous saccade. The response of the model to continuously varying inputs makes testable predictions for the performance of the vestibuloocular reflex. Our results suggest that dendritic bistability could stabilize the persistent neural activity observed in working memory systems.

CO2chemotransduction in central neurons: role of intracellular pH (pHi) and extracellular pH (pHo)

We have been studying the role of changes of pHi as part of the signaling pathway of hypercapnia in neonatal rat brainstem neurons from both chemosensitive (NTS-nucleus tractus solitarius, VLM-ventrolateral medulla, LC-locus coeruleus) and non-chemosensitive (IO-inferior olive, Hyp-hypoglossal) regions. We are testing the model of chemotransduction that proposes that hypercapnia acidifies neurons, which leads to inhibition of K+ channels, resulting in neuronal depolarization and increased firing rate. We measure pHi in individual neurons within brain slices using fluorescence imaging microscopy [1,2]. We developed a new technique to measure pHi and Vmsimultaneously by loading pH-sensitive fluorescent dyes using perforated patch (amphotericin B) pipettes in LC neurons [3]. All studies were done at 37°C. Neurons from all brainstem regions have high intrinsic buffering power, around 45 mM/pH unit for NTS, VLM, IO and Hyp neurons [1] and about 90 mM/pH unit for LC neurons [3]. The only pH-regulating transporter available for recovery from an acid load in these neurons is Na+/H+ exchange (NHE) [1,2]. The only HCO3-dependent transporter present is the acidifying Cl-/HCO3- exchanger, which has been found in VLM, IO, Hyp and some NTS neurons [1]. Interestingly, the NHE in neurons from chemosensitive regions (eg, NTS and VLM) is more sensitive to inhibition by decreased pHo than neurons from non-chemosensitive regions (eg, IO and Hyp) [1]. We observed different responses to hypercapnia in neurons from chemosensitive vs. non-chemosensitive regions. Hypercapnic acidosis (HA–10% CO2, pHo 7.15) resulted in a maintained fall of pHi in neurons from chemosensitive areas whereas pHi recovery from acidosis was evident in neurons from non-chemosensitive areas [2]. Under conditions of isohydric hypercapnia (IH–10% CO2, 52 mM HCO3-, pHo 7.45), pHi recovery was seen in neurons from all regions [2], indicating that pH-regulating mechanisms are present in all these neurons but that they are inhibited more fully by decreased pHo in neurons from chemosensitive regions. The same pHi responses to HA (15% CO2, pHo 6.8) and IH (15% CO2, 77 mM HCO3-, pHo 7.45) were seen in LC neurons where pHi and Vm were measured simultaneously. The changes of pHi ccurred before the changes in neuronal firing rate [3]. In LC neurons, HA resulted in a larger fall of pHi (0.27 vs. 0.15 pH unit) and a larger increase in firing rate (1.31 vs. 1.06 Hz) than seen with IH. Notably, increased firing rate was accompanied by membrane depolarization (2.5 mV) in response to HA but by membrane hyperpolarization (2.3 mV) in response to IH. Other acid challenges involving decreased pHo (acidified HEPES; isocapnic acidosis–5% CO2, 7 mM HCO3-, pHo 6.9) resulted in increased firing rate with depolarization while acid challenges involving constant pHo (50 mM propionate, pHo 7.45) resulted in slightly increased firing rate with membrane hyperpolarization. In summary, the response of Vm to a fall of pHi is dependent on whether changes or not and is not well correlated with pHo increased firing rate in LC neurons. The parameter that best correlates with increased firing rate in response to an acid challenge is the change of pHi, indicating that pHi is likely involved as part of the chemosensitive signaling pathway in LC neurons.

Replication and further studies of neural mechanisms of spatial mnemonic processing in humans

Changes in neuronal firing rates during periods of time when subjects are required to remember information (retention delays) have been reported in non-human primates. In humans, tests for such functional changes using hemodynamic markers of neural activity have typically relied on cognitive subtraction. However, the temporal resolution of fMRI allows a more direct test than that afforded by cognitive subtraction of the idea that certain brain regions may increase their neural activity during retention delays in humans. Using a method that exploits this temporal resolution, increased functional activity attributable to a retention delay for spatial information in regions proximate to/within the right frontal eye field and the right superior parietal lobule were detected (in four out of four and three out of four subjects, respectively; this is an internal replication of the results of [E. Zarahn, G.K. Aguirre, M. D’Esposito, Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI, Cognit. Brain Res., 7 (1999) 255–268.]). Second, a model in which ventral and not dorsal prefrontal cortex in humans is involved in simply maintaining spatial information was tested. The results disputed this model as increases in fMRI signal attributable to the retention delay were detected more frequently in dorsal than ventral prefrontal cortex. Third, a model which posited that the intensity of neural activity is causally related to the accuracy of spatial mnemonic representation was tested by comparing retention delay signal between correct and incorrect trials. The results did not support this model in any of the regions tested.