Firing Rate Of Cortical Neurons Research Articles

Choice selective inhibition drives stability and competition in decision circuits

During perceptual decision-making, the firing rates of cortical neurons reflect upcoming choices. Recent work showed that excitatory and inhibitory neurons are equally selective for choice. However, the functional consequences of inhibitory choice selectivity in decision-making circuits are unknown. We developed a circuit model of decision-making which accounts for the specificity of inputs to and outputs from inhibitory neurons. We found that selective inhibition expands the space of circuits supporting decision-making, allowing for weaker or stronger recurrent excitation when connected in a competitive or feedback motif. The specificity of inhibitory outputs sets the trade-off between speed and accuracy of decisions by either stabilizing or destabilizing the saddle-point dynamics underlying decisions in the circuit. Recurrent neural networks trained to make decisions display the same dependence on inhibitory specificity and the strength of recurrent excitation. Our results reveal two concurrent roles for selective inhibition in decision-making circuits: stabilizing strongly connected excitatory populations and maximizing competition between oppositely selective populations.

GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors.

GABA interneurons play a critical role in higher brain functions. Astrocytic glial cells interact with synapses throughout the whole brain and are recognized as regulatory elements of excitatory synaptic transmission. However, it is largely unknown how GABAergic interneurons and astrocytes interact and contribute to stable performance of complex behaviors. Here, we found that genetic ablation of GABAB receptors in medial prefrontal cortex astrocytes altered low-gamma oscillations and firing properties of cortical neurons, which affected goal-directed behaviors. Remarkably, working memory deficits were restored by optogenetic stimulation of astrocytes with melanopsin. Furthermore, melanopsin-activated astrocytes in wild-type mice enhanced the firing rate of cortical neurons and gamma oscillations, as well as improved cognition. Therefore, our work identifies astrocytes as a hub for controlling inhibition in cortical circuits, providing a novel pathway for the behaviorally relevant midrange time-scale regulation of cortical information processing and consistent goal-directed behaviors.

Axon initial segment plasticity accompanies enhanced excitation of visual cortical neurons in aged rats.

Recent studies have indicated that the structure of the axon initial segment (AIS) of neurons is highly plastic in response to changes in neuronal activity. Whether an age-related enhancement of neuronal responses in the visual cortex is coupled with plasticity of AISs is unknown. Here, we compare the AIS length and the distribution of Nav1.6, a key Na+ ion channel in action potential (AP) initiation, along the AIS of layer II/III neurons in the primary visual cortex (V1) of young adult and aged rats, which were examined previously in a single-unit recording study. In that study, we found that V1 neurons in aged rats showed a significantly higher spontaneous activity and stronger visually evoked responses than did neurons in young rats. Our present study shows that the mean AIS length of layer II/III neurons in the V1 area of aged rats was significantly shorter than that of young adult rats. Further, the proportion of AIS with the Nav1.6 distribution was also reduced significantly in aged rats relative to young rats, as indicated by a decrease in the mean Nav1.6 immunofluorescence optical density within AISs and a specific decrease in Nav1.6 immunofluorescence optical density near the proximal region of the AIS. Our results indicate that aging results in both shortening of AISs and reduction of Nav1.6 Na+ ion channel distribution along AISs, which accompanies enhanced neuronal activity. This age-related morphological plasticity may lower the AP amplitude by reducing Na+ ion entry during AP initiation, spare ATPs consumed by Na+ ion pumps during membrane potential restoration, and thus balance the energy expenditure caused by an increased firing rate of cortical neurons during the aging process.

Acute Inactivation of Primary Auditory Cortex Causes a Sound Localisation Deficit in Ferrets.

The objective of this study was to demonstrate the efficacy of acute inactivation of brain areas by cooling in the behaving ferret and to demonstrate that cooling auditory cortex produced a localisation deficit that was specific to auditory stimuli. The effect of cooling on neural activity was measured in anesthetized ferret cortex. The behavioural effect of cooling was determined in a benchmark sound localisation task in which inactivation of primary auditory cortex (A1) is known to impair performance. Cooling strongly suppressed the spontaneous and stimulus-evoked firing rates of cortical neurons when the cooling loop was held at temperatures below 10°C, and this suppression was reversed when the cortical temperature recovered. Cooling of ferret auditory cortex during behavioural testing impaired sound localisation performance, with unilateral cooling producing selective deficits in the hemifield contralateral to cooling, and bilateral cooling producing deficits on both sides of space. The deficit in sound localisation induced by inactivation of A1 was not caused by motivational or locomotor changes since inactivation of A1 did not affect localisation of visual stimuli in the same context.

Neural Resolution of Formant Frequencies in the Primary Auditory Cortex of Rats.

Pulse-resonance sounds play an important role in animal communication and auditory object recognition, yet very little is known about the cortical representation of this class of sounds. In this study we shine light on one simple aspect: how well does the firing rate of cortical neurons resolve resonant (“formant”) frequencies of vowel-like pulse-resonance sounds. We recorded neural responses in the primary auditory cortex (A1) of anesthetized rats to two-formant pulse-resonance sounds, and estimated their formant resolving power using a statistical kernel smoothing method which takes into account the natural variability of cortical responses. While formant-tuning functions were diverse in structure across different penetrations, most were sensitive to changes in formant frequency, with a frequency resolution comparable to that reported for rat cochlear filters.

Control of response reliability by parvalbumin-expressing interneurons in visual cortex.

The responses of visual cortical neurons to natural stimuli are both reliable and sparse. These properties require inhibition, yet the contribution of specific types of inhibitory neurons is not well understood. Here we demonstrate that optogenetic suppression of parvalbumin (PV)- but not somatostatin (SOM)-expressing interneurons reduces response reliability in the primary visual cortex of anaesthetized and awake mice. PV suppression leads to increases in the low firing rates and decreases in the high firing rates of cortical neurons, resulting in an overall reduction of the signal-to-noise ratio (SNR). In contrast, SOM suppression generally increases the overall firing rate for most neurons, without affecting the SNR. Further analysis reveals that PV, but not SOM, suppression impairs neural discrimination of natural stimuli. Together, these results reveal a critical role for PV interneurons in the formation of reliable visual cortical representations of natural stimuli.

Transcranial brain stimulation: potential and limitations

The brain adapts to new requirements in response to activity, learning or reactions to environmental stimuli by continuous reorganization. These reorganization processes can be facilitated and augmented, or also inhibited and prevented, by transcranial neurostimulation. The most common methods are electrical or magnetic stimulation. However, few studies have dealt with the newer methods using near infrared or ultrasound stimulation.Transcranial magnetic stimulation (TMS) allows the pain-free transfer of very short bursts of high intensity electrical energy through the skull and can induce action potentials. By varying the number and intensity of the stimuli, and the stimulus sequence, repetitive TMS (rTMS) can induce either inhibitory or facilitatory effects in the brain. A differentiation is made between short-lived interference with ongoing brain activity, and plastic changes that persist for a longer period beyond the end of the stimulation.Weaker electric fields in the 1 mA range can be applied painlessly through the skull. These probably exert their effects by modulating neuronal membranes and influencing the spontaneous firing rate of cortical neurons. They encompass the range from transcranial direct current stimulation (tDCS) to high frequency alternating current stimulation (tACS) in the kilohertz range. In view of the multitude of physically possible stimulation algorithms, hypothesis-driven protocols based on cellular or neuronal network characteristics are particularly popular, in the effort to narrow the choices in a meaningful manner. Examples are theta burst stimulation or tACS in the so-called “ripple” frequency range. It is, of course, not possible to selectively stimulate individual neurons using transcranial stimulation techniques; however selective after-effects can be achieved when used in combination with neuropharmacologically active drugs. The use of these methods for neuroenhancement is now a topic of intense discussion.

Computational modeling and analysis of hippocampal-prefrontal information coding during a spatial decision-making task

We introduce a computational model describing rat behavior and the interactions of neural populations processing spatial and mnemonic information during a maze-based, decision-making task. The model integrates sensory input and implements working memory to inform decisions at a choice point, reproducing rat behavioral data and predicting the occurrence of turn- and memory-dependent activity in neuronal networks subserving task performance. We tested these model predictions using a new software toolbox (Maze Query Language, MQL) to analyse activity of medial prefrontal cortical (mPFC) and dorsal hippocampal (dCA1) neurons recorded from six adult rats during task performance. The firing rates of dCA1 neurons discriminated context (i.e., the direction of the previous turn), whilst a subset of mPFC neurons was selective for current turn direction or context, with some conjunctively encoding both. mPFC turn-selective neurons displayed a ramping of activity on approach to the decision turn and turn-selectivity in mPFC was significantly reduced during error trials. These analyses complement data from neurophysiological recordings in non-human primates indicating that firing rates of cortical neurons correlate with integration of sensory evidence used to inform decision-making.

Balanced Excitatory and Inhibitory Synaptic Currents Promote Efficient Coding and Metabolic Efficiency

A balance between excitatory and inhibitory synaptic currents is thought to be important for several aspects of information processing in cortical neurons in vivo, including gain control, bandwidth and receptive field structure. These factors will affect the firing rate of cortical neurons and their reliability, with consequences for their information coding and energy consumption. Yet how balanced synaptic currents contribute to the coding efficiency and energy efficiency of cortical neurons remains unclear. We used single compartment computational models with stochastic voltage-gated ion channels to determine whether synaptic regimes that produce balanced excitatory and inhibitory currents have specific advantages over other input regimes. Specifically, we compared models with only excitatory synaptic inputs to those with equal excitatory and inhibitory conductances, and stronger inhibitory than excitatory conductances (i.e. approximately balanced synaptic currents). Using these models, we show that balanced synaptic currents evoke fewer spikes per second than excitatory inputs alone or equal excitatory and inhibitory conductances. However, spikes evoked by balanced synaptic inputs are more informative (bits/spike), so that spike trains evoked by all three regimes have similar information rates (bits/s). Consequently, because spikes dominate the energy consumption of our computational models, approximately balanced synaptic currents are also more energy efficient than other synaptic regimes. Thus, by producing fewer, more informative spikes approximately balanced synaptic currents in cortical neurons can promote both coding efficiency and energy efficiency.

Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states

Neocortical neurons mediate the sedative and anticonvulsant properties of benzodiazepines. These agents enhance synaptic inhibition via positive modulation of γ-aminobutyric acid (GABAA) receptors harboring α1-, α2-, α3- or α5-protein subunits. Benzodiazepine-sensitive GABAA receptors containing the α5-subunit are abundant in the neocortex, but their impact in controlling neuronal firing patterns is unknown. Here we studied how the discharge rates of cortical neurons are modified by a positive (SH-053-2′F-R-CH3) and a negative (L 655,708) α5-subunit-preferring allosteric modulator in comparison to diazepam, the classical non-selective benzodiazepine. Drug actions were characterized in slice cultures from wild-type and α5(H105R) knock-in mice by performing extracellular multi-unit-recordings. In knock-in mice, receptors containing the α5 subunit are insensitive to benzodiazepines. The non-selective positive allosteric modulator diazepam decreased the discharge rates of neocortical neurons during episodes of ongoing neuronal activity (up states). In contrast to diazepam, the α5-preferring positive modulator SH-053-2′F-R-CH3 accelerated action potential firing during up states. This promoting action was absent in slices from α5(H105R) mice, confirming that it is mediated by the α5-subunit. Consistent with these observations, the negative α5-selective modulator L 655,708 inhibited up state action potential activity in slices from wild-type mice. The opposing actions of diazepam and SH-053-2′F-R-CH3, which both enhance GABAA receptor function but differ in subtype-selectivity, uncovers contrasting roles of GABAA receptor subtypes in controlling the firing rates of cortical neurons. These findings may have important implications for the design of novel anaesthetic and anticonvulsant benzodiazepines displaying an improved efficacy and fewer side effects.

Propofol and Etomidate Depress Cortical, Thalamic, and Reticular Formation Neurons During Anesthetic-Induced Unconsciousness

The sites where anesthetics produce unconsciousness are not well understood. Likely sites include the cerebral cortex, thalamus, and reticular formation. We examined the effects of propofol and etomidate on neuronal function in the cortex, thalamus, and reticular formation in intact animals. Five cats had a recording well and electroencephalogram screws placed under anesthesia. After a 5-day recovery period, the cats were repeatedly studied 3 to 4 times per week. Neuronal (single-unit) activity in the cerebral cortex (areas 7, 18 and 19), thalamus (ventral posterolateral and ventral posteromedial nuclei and medial geniculate body), and reticular formation (mesencephalic reticular nucleus and central tegmental field) was recorded before, during, and after infusion of either propofol or etomidate. Cortical neuronal action potentials were analyzed separately as either regular spiking neurons or fast spiking neurons. Propofol and etomidate decreased the spontaneous firing rate of cortical neurons by 37% to 41%; fast spiking neurons and regular spiking neurons were similarly affected by the anesthetics. The neuronal firing rate in the thalamus and reticular formation decreased 30% to 49% by propofol and etomidate. The electroencephalogram shifted from a low-amplitude, high-frequency pattern to a high-amplitude, low-frequency pattern during drug infusion suggesting an anesthetic effect; peak power occurred at 12 to 13 Hz during propofol infusion. There were 2 major peaks during etomidate anesthesia: one at 12 to 14 Hz and another at 7 to 8 Hz. The cats were heavily sedated, with depressed corneal and whisker reflexes; withdrawal to noxious stimulation remained intact. These data show that neurons in the cortex, thalamus, and reticular formation are similarly depressed by propofol and etomidate. Although anesthetic depression of neuronal activity likely contributes to anesthetic-induced unconsciousness, further work is needed to determine how anesthetic effects at these sites interact to produce unconsciousness.

Interval Timing by Long-Range Temporal Integration

Interval Timing by Long-Range Temporal Integration

Impact of low intensity millimetre waves on cell functions

Investigations on the biological impact of low levels of millimetre-wave energy date back to the first experiments on the generation and detection of these high-frequency signals by Sir Jagadis Chunder Bose at the end of the 19th century. Slightly more than a hundred years later, millimetre-wave transmission has become a ubiquitous commercial reality. Despite the widespread use of millimetre-wave transmitters for communications, radar and even non-lethal weapons systems, only a handful of researchers have funded programmes focusing on millimetre-wave interactions with biological systems. As such, there is a growing need for a better understanding of the mechanisms of these interactions and their possible adverse and therapeutic implications. Independent of the health impact of long-term exposure to high doses of millimetre-wave energy on whole organisms, there exists the potential for subtle effects on specific tissues or organs which can best be quantified in studies which examine real-time changes in cellular function as energy is applied. In this Letter, a series of experiments are presented which show changes in cell membrane potential and the action potential firing rate of cortical neurons under short (1 min) exposures to continuous-wave 60 GHz radiation at µW/cm2 power levels, more than 1000 times below the US government maximum permissible exposure. The findings have implications for non-contact stimulation and control of neurologic function, and might prove useful in a variety of health applications from suppression of peripheral neuropathic pain to the treatment of central neurological disorders.

Mean field model of acetylcholine mediated dynamics in the thalamocortical system

A recent continuum model of the large scale electrical activity of the thalamocortical system is generalized to include cholinergic modulation. The model is examined analytically and numerically to determine the effect of acetylcholine (ACh) on its steady states, linear stability, spectrum, and temporal responses. Changing the ACh concentration moves the system between zones of one, three, and five steady states, showing that neuromodulation of synaptic strength is a possible mechanism by which multiple steady states emerge in the brain. The lowest firing rate steady state is always stable, and subsequent fixed points alternate between stable and unstable. Increasing ACh concentration changes the form of the spectrum. Increasing the tonic level of ACh concentration increases the magnitudes of the N100 and P200 in the evoked response potential (ERP), without changing the timing of these peaks. Driving the system with a pulse of cholinergic activity results in a transient increase in the firing rate of cortical neurons that lasts over 10 s . Step-like increases in cortical ACh concentration cause increases in the firing rate of cortical neurons, with rapid responses due to fast acting nicotinic receptors and slower responses due to muscarinic receptor suppression of intracortical connections.

Cortical activity patterns predict speech discrimination ability

Neural activity in the cerebral cortex can explain many aspects of sensory perception. Extensive psychophysical and neurophysiological studies of visual motion and vibrotactile processing show that the firing rate of cortical neurons averaged across 50-500 ms is well correlated with discrimination ability. In this study, we tested the hypothesis that primary auditory cortex (A1) neurons use temporal precision on the order of 1-10 ms to represent speech sounds shifted into the rat hearing range. Neural discrimination was highly correlated with behavioral performance on 11 consonant-discrimination tasks when spike timing was preserved and was not correlated when spike timing was eliminated. This result suggests that spike timing contributes to the auditory cortex representation of consonant sounds.

Mean field model of acetylcholine mediated dynamics in the cerebral cortex

A recent continuum model of the large scale electrical activity of the cerebral cortex is generalized to include cholinergic modulation. In this model, dynamic modulation of synaptic strength acts over the time scales of nicotinic and muscarinic receptor action. The cortical model is analyzed to determine the effect of acetylcholine (ACh) on its steady states, linear stability, spectrum, and temporal responses to changes in subcortical input. ACh increases the firing rate in steady states of the system. Changing ACh concentration does not introduce oscillatory behavior into the system, but increases the overall spectral power. Model responses to pulses in subcortical input are affected by the tonic level of ACh concentration, with higher levels of ACh increasing the magnitude firing rate response of excitatory cortical neurons to pulses of subcortical input. Numerical simulations are used to explore the temporal dynamics of the model in response to changes in ACh concentration. Evidence is seen of a transition from a state in which intracortical inputs are emphasized to a state where thalamic afferents have enhanced influence. Perturbations in ACh concentration cause changes in the firing rate of cortical neurons, with rapid responses due to fast acting facilitatory effects of nicotinic receptors on subcortical afferents, and slower responses due to muscarinic suppression of intracortical connections. Together, these numerical simulations demonstrate that the actions of ACh could be a significant factor modulating early components of evoked response potentials.

Evidence for Activity-Dependent Cortical Wiring: Formation of Interhemispheric Connections in Neonatal Mouse Visual Cortex Requires Projection Neuron Activity

Neuronal activity plays a pivotal role in shaping neuronal wiring. We investigated the role of neuronal activity in the formation of interhemispheric (callosal) axon projections in neonatal mouse visual cortex. Axonal labeling with enhanced green fluorescent protein (GFP) was used to demonstrate spatially organized pattern of callosal projections: GFP-labeled callosal axons from one hemisphere projected densely to a narrowly restricted region at the border between areas 17 and 18 in the contralateral hemisphere, in which they terminated in layers 1-3 and 5. This region- and layer-specific innervation pattern developed by postnatal day 15 (P15). To explore the role of neuronal activity of presynaptic and postsynaptic neurons in callosal connection development, an inwardly rectifying potassium channel, Kir2.1, was expressed in callosal projection neurons and their target postsynaptic neurons. Kir2.1 overexpression reduced the firing rate of cortical neurons. Kir2.1 overexpression in callosal projection neurons disturbed the growth of axons and their arbors that normally occurs between P7 and P13, whereas that in postsynaptic neurons had limited effect on the pattern of presynaptic callosal axon innervation. In addition, exogenous expression of a gain-of-function Kir2.1 mutant channel found in patients with a familial heart disease caused severe deficits in callosal axon projections. These results suggest that projection neuron activity plays a crucial role in interhemispheric connection development and that enhanced Kir2.1 activity can affect cortical wiring.

Dynamic Gain Changes During Attentional Modulation

Attention causes a multiplicative effect on firing rates of cortical neurons without affecting their selectivity (Motter, 1993; McAdams & Maunsell, 1999a) or the relationship between the spike count mean and variance (McAdams & Maunsell, 1999b). We analyzed attentional modulation of the firing rates of 144 neurons in the secondary somatosensory cortex (SII) of two monkeys trained to switch their attention between a tactile pattern recognition task and a visual task. We found that neurons in SII cortex also undergo a predominantly multiplicative modulation in firing rates without affecting the ratio of variance to mean firing rate (i.e., the Fano factor). Furthermore, both additive and multiplicative components of attentional modulation varied dynamically during the stimulus presentation. We then used a standard conductance-based integrate-and-fire model neuron to ascertain which mechanisms might account for a multiplicative increase in firing rate without affecting the Fano factor. Six mechanisms were identified as biophysically plausible ways that attention could modify the firing rate: spike threshold, firing rate adaptation, excitatory input synchrony, synchrony between all inputs, membrane leak resistance, and reset potential. Of these, only a change in spike threshold or in firing rate adaptation affected model firing rates in a manner compatible with the observed neural data. The results indicate that only a limited number of biophysical mechanisms can account for observed attentional modulation.

Effects of Task Difficulty and Target Likelihood in Area V4 of Macaque Monkeys

Spatial attention improves performance at attended locations and correspondingly modulates firing rates of cortical neurons. The size of these behavioral and neuronal effects depends on the difficulty of the task performed at the attended location. Psychological theorists have attributed this to a tighter focus of a fixed amount of processing resource at the attended location, but the effects of task difficulty on the distribution of neuronal effects of attention across the visual field have not been fully explored. We trained rhesus monkeys to do a detection task in which difficulty and spatial attention were manipulated independently. Probe stimuli were used to measure behavioral performance in different conditions of attention and difficulty. Animals performed better at attended locations and this advantage increased with difficulty, consistent with data from human psychophysics. Neuronal modulation by spatial attention was larger with greater difficulty. In two animals, increasing difficulty caused a modest increase in neuronal responses to visual stimuli regardless of the locus of spatial attention. In a third animal, which was previously trained to ignore multiple distracting stimuli, increasing task difficulty increased responses at the focus of attention and suppressed responses away from the focus of attention. The results show that difficulty can modulate effects of spatial attention in V4; it can alter the distribution of sensory responses across the visual scene in ways that may depend on the subject's behavioral strategy.

The application of in vivo microiontophoresis for the investigation of mast cell–neuron interactions in the rat brain

Although mast cells are immune cells of hematopoietic origin, they can be found in parts of the central nervous system of many mammalian species. In the rat brain they are located in the thalamic region. Their function is not defined yet, although they are mostly known to secrete several chemicals, which may influence the surrounding neurons. There are no in vivo electrophysiological data available on the possible effects of brain mast cells on neurons. In this study, we used a combined method of microiontophoresis and extracellular single unit recording to simultaneously activate mast cells and record neuronal action potentials. Four-barrelled micropipettes were used for recording neuronal activity and for microiontophoretic application of mast cell degranulator Compound 48/80 (C48/80). Spike sorting routines were performed on-line and off-line to ensure that data were always recorded from a single neuron. C48/80 did not modify the firing rate of cortical neurons (no mast cells are found there), however, it caused excitation ( n = 16/37, 43%), or inhibition ( n = 9/37, 24%) in thalamic neurons possibly due to mast cell activation. Further investigations will clarify the biochemical nature of changes in neural excitability due to mast cell degranulation in the mammalian brain.