Burst Firing Properties Research Articles

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice.

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

Comparison of alterations in local field potentials and neuronal firing in mouse M1 and CA1 associated with central fatigue induced by high-intensity interval training and moderate-intensity continuous training.

The mechanisms underlying central fatigue (CF) induced by high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are still not fully understood. In order to explore the effects of these exercises on the functioning of cortical and subcortical neural networks, this study investigated the effects of HIIT and MICT on local field potential (LFP) and neuronal firing in the mouse primary motor cortex (M1) and hippocampal CA1 areas. HIIT and MICT were performed on C57BL/6 mice, and simultaneous multichannel recordings were conducted in the M1 motor cortex and CA1 hippocampal region. A range of responses were elicited, including a decrease in coherence values of LFP rhythms in both areas, and an increase in slow and a decrease in fast power spectral density (PSD, n = 7-9) respectively. HIIT/MICT also decreased the gravity frequency (GF, n = 7-9) in M1 and CA1. Both exercises decreased overall firing rates, increased time lag of firing, declined burst firing rates and the number of spikes in burst, and reduced burst duration (BD) in M1 and CA1 (n = 7-9). While several neuronal firing properties showed a recovery tendency, the alterations of LFP parameters were more sustained during the 10-min post-HIIT/MICT period. MICT appeared to be more effective than HIIT in affecting LFP parameters, neuronal firing rate, and burst firing properties, particularly in CA1. Both exercises significantly affected neural network activities and local neuronal firing in M1 and CA1, with MICT associated with a more substantial and consistent suppression of functional integration between M1 and CA1. Our study provides valuable insights into the neural mechanisms involved in exercise-induced central fatigue by examining the changes in functional connectivity and coordination between the M1 and CA1 regions. These findings may assist individuals engaged in exercise in optimizing their exercise intensity and timing to enhance performance and prevent excessive fatigue. Additionally, the findings may have clinical implications for the development of interventions aimed at managing conditions related to exercise-induced fatigue.

Different adaptations of dopamine release in Nucleus Accumbens shell and core of individual alcohol drinking groups of mice

Alcohol use disorder (AUD) places a tremendous burden on society, with approximately two billion alcohol users in the world. While most people drink alcohol recreationally, a subpopulation (3–5%) engages in reckless and compulsive drinking, leading to the development of AUD and alcohol dependence. The Ventral Tegmental Area (VTA)-Nucleus Accumbens (NAc) circuit has been shown to encode rewarding stimuli and drive individual alcohol drinking behavior. Our previous work successfully separated C57BL/6J isogenic mice into high or low alcohol drinking subgroups after a 12-day, two-bottle choice voluntary alcohol access paradigm. Electrophysiological studies revealed that low alcohol drinking mice exhibited elevated spontaneous and burst firing properties of their VTA dopamine (DA) neurons and specifically mimicking this pattern of activity in VTA-NAc neurons in high alcohol drinking mice using optogenetics decreased their alcohol preference. It is also known that VTA DA neurons encode the salience and rewarding properties of external stimuli while also regulating downstream dopamine concentrations. Here, as a follow-up to this study, we utilized Fast Scan Cyclic Voltammetry (FSCV) to examine dopamine release in the NAc shell and core between alcohol drinking groups. We observed dynamic changes of dopamine release in the core of high drinking mice, but failed to see widely significant differences of dopamine release in the shell of both groups, when compared with ethanol-naive controls. Overall, the present data suggest subregion-specific differences of evoked dopamine release in the NAc of low and high alcohol drinking mice, and may provide an anatomical substrate for individual alcohol drinking behavior.This article is part of the special issue on Stress, Addiction and Plasticity.

A Computational Modeling Reveals That Strength of Inhibitory Input, E/I Balance, and Distance of Excitatory Input Modulate Thalamocortical Bursting Properties.

The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations—proximal, intermediate, or distal—of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.

Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum

BackgroundHypnotics and general anaesthetics impair memory by altering hippocampal synaptic plasticity. We recently reported on a neurosteroid analogue with potent hypnotic activity [(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile; 3β-OH], which does not cause developmental neurotoxicity in rat pups. Here, we investigated the effects of 3β-OH on neuronal excitability in the subiculum, the major output structure of the hippocampal formation, and synaptic plasticity at two key hippocampal synapses in juvenile rats. MethodsBiophysical properties of isolated T-type calcium currents (T-currents) in the rat subiculum were investigated using acute slice preparations. Subicular T-type calcium channel (T-channel) subtype mRNA expression was compared using qRT–PCR. Using electrophysiological recordings, we examined the effects of 3β-OH and an endogenous neuroactive steroid, allopregnanolone (Allo), on T-currents and burst firing properties of subicular neurones, and on the long-term potentiation (LTP) in CA3-CA1 and CA1-subiculum pathways. ResultsBiophysical and molecular studies confirmed that CaV3.1 channels represent the dominant T-channel isoform in the subiculum of juvenile rats. 3β-OH and Allo inhibited rebound burst firing by decreasing the amplitude of T-currents in a voltage-dependent manner with similar potency, with 30–80% inhibition. Both neurosteroids suppressed LTP at the CA1-subiculum, but not at the CA3-CA1 Schaffer collateral synapse. ConclusionsNeurosteroid effects on T-channels modulate hippocampal output and provide possible molecular mechanisms for the amnestic action of the novel hypnotic 3β-OH. Effects on T-channels in the subiculum provide a novel target for amnestic effects of hypnotics.

Alterations in the Intrinsic Burst Activity of Purkinje Neurons in Offspring Maternally Exposed to the CB1 Cannabinoid Agonist WIN 55212-2

Burst firing plays an important role in normal neuronal function and dysfunction. In Purkinje neurons, where the firing rate and discharge pattern encode the timing signals necessary for motor function, any alteration in firing properties, including burst activity, may affect the motor output. Therefore, we examined whether maternal exposure to the cannabinoid receptor agonist WIN 55212-2 (WIN) may affect the burst firing properties of cerebellar Purkinje cells in offspring. Whole-cell somatic patch-clamp recordings were made from cerebellar slices of adult male rats that were exposed to WIN prenatally. WIN exposure during pregnancy induced long-term alterations in the burst firing behavior of Purkinje neurons in rat offspring as evidenced by a significant increase in the mean number of spikes per burst (p<0.05) and the prolongation of burst firing activity (p<0.01). The postburst afterhyperpolarization potential (p<0.001), the mean intraburst interspike intervals (p<0.001) and the mean intraburst firing frequency (p<0.001) were also significantly increased in the WIN-treated group. Prenatal exposure to WIN enhanced the firing irregularity as reflected by a significant decrease in the coefficient of variation of the intraburst interspike interval (p<0.05). Furthermore, whole-cell voltage-clamp recordings revealed that prenatal WIN exposure significantly enhanced Ca(2+) channel current amplitude in offspring Purkinje neurons compared to control cells. Overall, the data presented here strongly suggest that maternal exposure to cannabinoids can induce long-term changes in complex spike burst activity, which in turn may lead to alterations in neuronal output.

Discrete Pattern of Burst Stimulation in the Ventrobasal Thalamus for Anti-Nociception

The thalamus has been proposed to play a role in sensory modulation via switching between tonic and burst dual firing of individual neurons. Of the two firing modes, altered burst firing has been repeatedly implicated with pathological pain conditions, which suggests that maintaining a certain form of thalamic burst could be crucial for controlling pain. However, specific elements of burst firing that may contribute to pain control have not yet been actively investigated. Utilizing the deep brain stimulation (DBS) technique, we explored the effects of bursting properties in pain control by electrically stimulating the ventrobasal (VB) thalamus in forms of burst patterned to test different aspects of bursts during the formalin induced nociception in mice. Our results demonstrated that electrical stimulations mimicking specific burst firing properties are important in producing an anti-nociceptive effect and found that the ≤3 ms interval between burst pluses (intra-burst-interval: IntraBI) and ≥3 pulses per burst were required to reliably reduce formalin induced nociceptive responses in mice. Periodicity of IntraBI was also suggested to contribute to anti-nociception to a limited extent.

High-frequency stimulation in the ventral posterolateral thalamus reverses electrophysiologic changes and hyperalgesia in a rat model of peripheral neuropathic pain

Chronic neuropathic pain is associated with long-term changes at multiple levels of the neuroaxis, including in the brain, where electrical stimulation has been used to manage severe pain conditions. However, the clinical outcome of deep brain stimulation is often mixed, and the mechanisms are poorly understood. By means of electrophysiologic methods, we sought to characterize the changes in neuronal activity in the ventral posterolateral nucleus of the thalamus (VPL) in a rat model of peripheral neuropathic pain, and to reverse these changes with low-voltage, high-frequency stimulation (HFS) in the VPL. Extracellular single-unit neuronal activity was recorded in naive rats and in those with sciatic chronic constriction injury (CCI). Seven days after CCI, brush- and pinch-evoked firing, as well as spontaneous firing and afterdischarge, were significantly increased compared to naive rats. Spontaneous rhythmic oscillation in neuronal firing was also observed in rats with CCI. HFS decreased neuronal firing rates in rats with CCI up to ∼50% except for spontaneous activity, whereas low-frequency stimulation had no effect. Compared to naive rats, burst firing properties (burst events, percentage of spikes in burst, and mean interburst time) were altered in rats with CCI, whereas these changes were reversed to near normal after HFS. Thermal hyperalgesia in rats with CCI was significantly attenuated by HFS. Therefore, this study demonstrates that electrical stimulation within the VPL can effectively modulate some nociceptive phenomena associated with peripheral neuropathic pain.

Intron retention facilitates splice variant diversity in calcium-activated big potassium channel populations

We report that the stress axis-regulated exon (STREX)-containing calcium-activated big potassium (BKCa) channel splice variant expression and physiology are regulated in part by cytoplasmic splicing and intron retention. NextGen sequencing of the mRNA complement of pooled hippocampal dendrite samples found intron 17a (i17a), the intron immediately preceding STREX, in the BKCa mRNA. Further molecular analyses of i17a revealed that the majority of i17a-containing BKCa channel mRNAs associate with STREX. i17a siRNA treatment followed by STREX protein immunocytochemistry demonstrated both reduced levels and altered subcellular distribution of STREX-containing BKCa channel protein. Selective reduction of i17a-BKCa or STREX-BKCa mRNAs induced similar changes in the burst firing properties of hippocampal neurons. Collectively, these data show that STREX splice variant regulation via cytoplasmic splicing and intron retention helps generate STREX-dependent BKCa current diversity in hippocampal neurons.

Neural Heterogeneities and the coding of contrast envelopes

It is well known that higher order neurons respond to contrast envelopes (second order statistics) present in sensory stimuli. These contrast envelopes can be defined as the curve connecting successive peaks in the stimulus and can only be obtained through a nonlinear transformation of the stimulus such as the Hilbert transform. They contain important information that is decoded by the brain: for example, removal of these envelopes from speech severely reduces its intelligibility. While recent studies have shown potential mechanisms by which higher order neurons can acquire sensitivity to contrast envelopes, it is generally thought that peripheral sensory neurons do not respond to them. Using the electrosensory system of the weakly electric fish as a model we performed extracellular recordings from primary afferents while presenting contrast-modulated random amplitude modulations (AMs) of the fish’s quasi-sinusoidal electric field and found that about 45% of units responded to the time varying contrast envelope. Previous studies have shown that these afferents are spontaneously active and display large heterogeneities in their firing rates and burst firing properties: we therefore investigated whether these heterogeneities are linked to contrast envelope coding. We found that afferents with low spontaneous firing rate responded best to the contrast envelope due to higher levels of rectification. We next investigated the basis of this higher level of rectification using a simple phenomenological model of primary afferent activity. We found that varying levels of intrinsic noise as well as overall bias current in our model could reproduce our experimental results, suggesting that neural heterogeneities can significantly influence contrast envelope coding at the sensory periphery.

Physiological and Morphological Characterization of Local Interneurons in the Drosophila Antennal Lobe

The Drosophila antennal lobe (AL) has become an excellent model for studying early olfactory processing mechanisms. Local interneurons (LNs) connect a large number of glomeruli and are ideally positioned to increase computational capabilities of odor information processing in the AL. Although the neural circuit of the Drosophila AL has been intensively studied at both the input and the output level, the internal circuit is not yet well understood. An unambiguous characterization of LNs is essential to remedy this lack of knowledge. We used whole cell patch-clamp recordings and characterized four classes of LNs in detail using electrophysiological and morphological properties at the single neuron level. Each class of LN displayed unique characteristics in intrinsic electrophysiological properties, showing differences in firing patterns, degree of spike adaptation, and amplitude of spike afterhyperpolarization. Notably, one class of LNs had characteristic burst firing properties, whereas the others were tonically active. Morphologically, neurons from three classes innervated almost all glomeruli, while LNs from one class innervated a specific subpopulation of glomeruli. Three-dimensional reconstruction analyses revealed general characteristics of LN morphology and further differences in dendritic density and distribution within specific glomeruli between the different classes of LNs. Additionally, we found that LNs labeled by a specific enhancer trap line (GAL4-Krasavietz), which had previously been reported as cholinergic LNs, were mostly GABAergic. The current study provides a systematic characterization of olfactory LNs in Drosophila and demonstrates that a variety of inhibitory LNs, characterized by class-specific electrophysiological and morphological properties, construct the neural circuit of the AL.

Alterations in Burst Firing of Thalamic VPL Neurons and Reversal by Nav1.3 Antisense After Spinal Cord Injury

We recently showed that spinal cord contusion injury (SCI) at the thoracic level induces pain-related behaviors and increased spontaneous discharges, hyperresponsiveness to innocuous and noxious peripheral stimuli, and enlarged receptive fields in neurons in the ventral posterolateral (VPL) nucleus of the thalamus. These changes are linked to the abnormal expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel. In this study, we examined the burst firing properties of VPL neurons after SCI. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 level. Four weeks later, when Na(v)1.3 protein was upregulated within VPL neurons, extracellular unit recordings were made from VPL neurons in intact animals, those with SCI, and in SCI animals after receiving lumbar intrathecal injections of Na(v)1.3 antisense or mismatch oligodeoxynucleotides for 4 days. After SCI, VPL neurons with identifiable peripheral receptive fields showed rhythmic oscillatory burst firing with changes in discrete burst properties, and alternated among single-spike, burst, silent, and spindle wave firing modes. Na(v)1.3 antisense, but not mismatch, partially reversed alterations in burst firing after SCI. These results demonstrate several newly characterized changes in spontaneous burst firing properties of VPL neurons after SCI and suggest that abnormal expression of Na(v)1.3 contributes to these phenomena.

Low threshold calcium spikes in medial vestibular nuclei neurones in vitro: a role in the generation of the vestibular nystagmus quick phase in vivo?

Intracellular recordings were obtained from medial vestibular nuclei neurones in guinea-pig brainstem slices. A subpopulation of neurones in this nucleus was found to have burst firing properties. Using ionic channel blockers the underlying mechanism was shown to be a low threshold calcium spike. It is speculated that this property could be implicated in the generation of the quick phase of the vestibular nystagmus in the behaving guinea-pig.