Neuronal Firing Research Articles

Dynamic spatial representation of self and others’ actions in the macaque frontal cortex

Modulation of neuronal firing rates by the spatial locations of physical objects is a widespread phenomenon in the brain. However, little is known about how neuronal responses to the actions of biological entities are spatially tuned and whether such spatially tuned responses are affected by social contexts. These issues are of key importance for understanding the neural basis of embodied social cognition, such as imitation and perspective-taking. Here, we show that spatial representation of actions can be dynamically changed depending on others' social relevance and agents of action. Monkeys performed a turn-taking choice task with a real monkey partner sitting face-to-face or a filmed partner in prerecorded videos. Three rectangular buttons (left, center, and right) were positioned in front of the subject and partner as their choice targets. We recorded from single neurons in two frontal nodes in the social brain, the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC). When the partner was filmed rather than real, spatial preference for partner-actions was markedly diminished in MPFC, but not PMv, neurons. This social context-dependent modulation in the MPFC was also evident for self-actions. Strikingly, a subset of neurons in both areas switched their spatial preference between self-actions and partner-actions in a diametrically opposite manner. This observation suggests that these cortical areas are associated with coordinate transformation in ways consistent with an actor-centered perspective-taking coding scheme. The PMv may subserve such functions in context-independent manners, whereas the MPFC may do so primarily in social contexts.

Motor Learning in a Complex Motor Task Is Unaffected by Three Consecutive Days of Transcranial Alternating Current Stimulation.

Transcranial alternating current stimulation (tACS) delivered to the primary motor cortex (M1) can increase cortical excitability, entrain neuronal firing patterns, and increase motor skill acquisition in simple motor tasks. The primary aim of this study was to assess the impact of tACS applied to M1 over three consecutive days of practice on the motor learning of a challenging overhand throwing task in young adults. The secondary aim was to examine the influence of tACS on M1 excitability. This study implemented a double-blind, randomized, SHAM-controlled, between-subjects experimental design. A total of 24 healthy young adults were divided into tACS and SHAM groups and performed three identical experimental sessions that comprised blocks of overhand throwing trials of the right dominant arm concurrent with application of tACS to the left M1. Performance in the overhand throwing task was quantified as the endpoint error. Motor evoked potentials (MEPs) were assessed in the right first dorsal interosseus (FDI) muscle with transcranial magnetic stimulation (TMS) to quantify changes in M1 excitability. Endpoint error was significantly decreased in the post-tests compared with the pre-tests when averaged over the three days of practice (p = 0.046), but this decrease was not statistically significant between the tACS and SHAM groups (p = 0.474). MEP amplitudes increased from the pre-tests to the post-tests (p = 0.003), but these increases were also not different between groups (p = 0.409). Overall, the main findings indicated that tACS applied to M1 over multiple days does not enhance motor learning in a complex task to a greater degree than practice alone (SHAM).

Epilepsy-associated Kv1.1 channel subunits regulate intrinsic cardiac pacemaking in mice.

The heartbeat originates from spontaneous action potentials in specialized pacemaker cells within the sinoatrial node (SAN) of the right atrium. Voltage-gated potassium channels in SAN myocytes mediate outward K+ currents that regulate cardiac pacemaking by controlling action potential repolarization, influencing the time between heartbeats. Gene expression studies have identified transcripts for many types of voltage-gated potassium channels in the SAN, but most remain of unknown functional significance. One such gene is Kcna1, which encodes epilepsy-associated voltage-gated Kv1.1 K+ channel α-subunits that are important for regulating action potential firing in neurons and cardiomyocytes. Here, we investigated the functional contribution of Kv1.1 to cardiac pacemaking at the whole heart, SAN, and SAN myocyte levels by performing Langendorff-perfused isolated heart preparations, multielectrode array recordings, patch clamp electrophysiology, and immunocytochemistry using Kcna1 knockout (KO) and wild-type (WT) mice. Our results showed that either genetic or pharmacological ablation of Kv1.1 significantly decreased the SAN firing rate, primarily by impairing SAN myocyte action potential repolarization. Voltage-clamp electrophysiology and immunocytochemistry revealed that Kv1.1 exerts its effects despite contributing only a small outward K+ current component, which we term IKv1.1, and despite apparently being present in low abundance at the protein level in SAN myocytes. These findings establish Kv1.1 as the first identified member of the Kv1 channel family to play a role in sinoatrial function, thereby rendering it a potential candidate and therapeutic targeting of sinus node dysfunction. Furthermore, our results demonstrate that small currents generated via low-abundance channels can still have significant impacts on cardiac pacemaking.

Caspase-1 inhibitor CZL80 protects against acute seizures via amplifying the inhibitory neural transmission

Current anti-seizure medications (ASDs) primarily target ion channels or neurotransmissions; however, their practicability is limited by unwanted side-effects and pharmacoresistance. Cumulative evidence has proposed pro-inflammatory caspase-1 as a potential target for developing ASDs. In this study, we showed that the small-molecular caspase-1 inhibitor CZL80 can prevent seizures in various models including the maximal electroshock (MES), the pentylenetetrazol (PTZ), and the amygdaloid kindled models. Specifically, we discovered that CZL80 prevented death, reduced the duration of generalized seizures, and increased the threshold of generalized seizures in a dose-dependent manner in the MES model. In the PTZ model, CZL80 decreased the seizure stages, prolonged the latency to stage 4 seizures, and decreased the death rate. And in amygdaloid kindled rats, CZL80 inhibited the seizure stages, shortened the durations of both generalized seizures and after-discharges. And the anti-seizure efficacy of CZL80 was diminished in caspase-1 knockout mice. In vitro electrophysiology recordings revealed that CZL80 was able to decreased the excitability of glutamatergic pyramidal neurons, as denoted by reducing the spontaneous neuronal firings and increasing the rheobase injected currents to elicit action potentials. Furthermore, CZL80 was able to increase the amplitudes of inhibitory post-synaptic currents (IPSC), while the excitatory post-synaptic currents (EPSC) were not influenced. Lastly, daily administration of CZL80 for 3 weeks did not influence the normal locomotor functions in mice. In sum, our results highlighted CZL80 as a potential anti-seizure therapy with therapeutic significance.

Contributions of cortical neuron firing patterns, synaptic connectivity, and plasticity to task performance

Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular ‘non-classically responsive’ firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Dynamical analysis of a discrete Aihara neuron under a locally active memristor as electromagnetic radiation and its DSP implementation

The study of neuron model under electromagnetic radiation is significant for learning brain principles and treating mental diseases. In this paper, a novel discrete locally active memristor(DLAM) model is designed and its characteristics are investigated thoroughly. Then, the DLAM is used to imitate electromagnetic radiation to stimulate Aihara neuron, called EMR-Aihara neuron model. The equilibrium point of this discrete model is analyzed. Dynamical characteristics are studied by means of phase diagram, iteration sequence, bifurcation diagram, Lyapunov Exponent spectrum(LEs), Kolmogorow entropy(KE) and Spectral Entropy(SE) complexity. With these analysis methods, rich dynamical behaviors and neuron firing patterns are discovered from the EMR-Aihara neuron map, including hyperchaos, chaos and period. In addition, complex multistability and state transition phenomena concerning various attractors and neuron firing modes are observed. This EMR-Aihara neuron map is implemented in digital circuit by DSP platform as well, confirming the physical availability of the model. The EMR-Aihara neuron model can simulate biological neuron under electromagnetic radiation and apply to image encryption.

Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture

Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.

Sulfonylurea receptor coupled conductances alter the performace of two central pattern generating circuits in Cancer borealis.

Neuronal activity and energy supply must maintain a fine balance for neuronal fitness. Various channels of communication between the two could impact network output in different ways. Sulfonylurea receptors (SURs) are a modification of ATP-binding cassette proteins (ABCs) that confer ATP-dependent gating on their associated ion channels. They are widely expressed and link metabolic states directly to neuronal activity. The role they play varies in different circuits, both enabling bursting and inhibiting activity in pathological conditions. The crab, Cancer borealis, has central patterns generators (CPGs) that fire in rhythmic bursts nearly constantly and it is unknown how energy availability influences these networks. The pyloric network of the stomatogastric ganglion (STG) and cardiac ganglion (GC) control rhythmic contractions of the foregut and heart respectively. Pharmacological manipulation of SURs results in opposite effects in the two CPGs. Neuronal firing completely stops in the STG when SUR-associated channels are open, and firing increases when the channels are closed. This results from a decrease in the excitability of pyloric dilator (PD) neurons, which are a part of the pacemaker kernel. The neurons of the CG, paradoxically, increase firing within bursts when SUR-associated channels are opened, and bursting slows when SUR-associated channels are closed. The channel permeability and sensitivities analyses present novel SUR-conductance biophysics, which nevertheless change activity in ways reminiscent of the predominantly studied mammalian receptor/channels. We suggest that SUR-associated conductances allow different neurons to respond to energy states in different ways through a common mechanism.

Initial and corrective submovement encoding differences within primary motor cortex during precision reaching.

Precision reaching often requires corrective submovements to obtain the desired goal. Most studies of reaching have focused on single initial movements, and implied the cortical encoding model was the same for all submovements. However, corrective submovements may show different encoding patterns from the initial submovement with distinct patterns of activation across the population. Two rhesus macaques performed a precision center-out-task with small targets. Neural activity from single units in the primary motor cortex and associated behavioral data were recorded to evaluate movement characteristics. Neural population data and individual neuronal firing rates identified with a peak finding algorithm to identify peaks in hand speed were examined for encoding differences between initial and corrective submovements. Individual neurons were fitted with a regression model that included the reach vector, position, and speed to predict firing rate. For both initial and corrective submovements, the largest effect remained movement direction. We observed a large subset changed their preferred direction greater than 45° between initial and corrective submovements. Neuronal depth of modulation also showed considerable variation when adjusted for movement speed. By using principal component analysis, neural trajectories of initial and corrective submovements progressed through different neural subspaces. These findings all suggest that different neural encoding patterns exist for initial and corrective submovements within the cortex. We hypothesize that this variation in how neurons change to encode small, corrective submovements might allow for a larger portion of the neural space being used to encode a greater range of movements with varying amplitudes and levels of precision.NEW & NOTEWORTHY Neuronal recordings matched with kinematic behavior were collected in a precision center-out task that often required corrective movements. We reveal large differences in preferred direction and depth of modulation between initial and corrective submovements across the neural population. We then present a model of the neural population describing how these shifts in tuning create different subspaces for signaling initial and corrective movements likely to improve motor precision.

Synaptic reorganization of synchronized neuronal networks with synaptic weight and structural plasticity.

Abnormally strong neural synchronization may impair brain function, as observed in several brain disorders. We computationally study how neuronal dynamics, synaptic weights, and network structure co-emerge, in particular, during (de)synchronization processes and how they are affected by external perturbation. To investigate the impact of different types of plasticity mechanisms, we combine a network of excitatory integrate-and-fire neurons with different synaptic weight and/or structural plasticity mechanisms: (i) only spike-timing-dependent plasticity (STDP), (ii) only homeostatic structural plasticity (hSP), i.e., without weight-dependent pruning and without STDP, (iii) a combination of STDP and hSP, i.e., without weight-dependent pruning, and (iv) a combination of STDP and structural plasticity (SP) that includes hSP and weight-dependent pruning. To accommodate the diverse time scales of neuronal firing, STDP, and SP, we introduce a simple stochastic SP model, enabling detailed numerical analyses. With tools from network theory, we reveal that structural reorganization may remarkably enhance the network's level of synchrony. When weaker contacts are preferentially eliminated by weight-dependent pruning, synchrony is achieved with significantly sparser connections than in randomly structured networks in the STDP-only model. In particular, the strengthening of contacts from neurons with higher natural firing rates to those with lower rates and the weakening of contacts in the opposite direction, followed by selective removal of weak contacts, allows for strong synchrony with fewer connections. This activity-led network reorganization results in the emergence of degree-frequency, degree-degree correlations, and a mixture of degree assortativity. We compare the stimulation-induced desynchronization of synchronized states in the STDP-only model (i) with the desynchronization of models (iii) and (iv). The latter require stimuli of significantly higher intensity to achieve long-term desynchronization. These findings may inform future pre-clinical and clinical studies with invasive or non-invasive stimulus modalities aiming at inducing long-lasting relief of symptoms, e.g., in Parkinson's disease.

Dopamine Release in the Nucleus Accumbens Core Encodes the General Excitatory Components of Learning.

Dopamine release in the nucleus accumbens core (NAcC) is generally considered to be a proxy for phasic firing of the ventral tegmental area dopamine (VTADA) neurons. Thus, dopamine release in NAcC is hypothesized to reflect a unitary role in reward prediction error signaling. However, recent studies reveal more diverse roles of dopamine neurons, which support an emerging idea that dopamine regulates learning differently in distinct circuits. To understand whether the NAcC might regulate a unique component of learning, we recorded dopamine release in NAcC while male rats performed a backward conditioning task where a reward is followed by a neutral cue. We used this task because we can delineate different components of learning, which include sensory-specific inhibitory and general excitatory components. Furthermore, we have shown that VTADA neurons are necessary for both the specific and general components of backward associations. Here, we found that dopamine release in NAcC increased to the reward across learning while reducing to the cue that followed as it became more expected. This mirrors the dopamine prediction error signal seen during forward conditioning and cannot be accounted for temporal-difference reinforcement learning. Subsequent tests allowed us to dissociate these learning components and revealed that dopamine release in NAcC reflects the general excitatory component of backward associations, but not their sensory-specific component. These results emphasize the importance of examining distinct functions of different dopamine projections in reinforcement learning.

The Kv7 channel opener Retigabine reduces neuropathology and alleviates behavioral deficits in APP/PS1 transgenic mice

Hyperexcitability of neuronal networks is central to the pathogenesis of Alzheimer's disease (AD). Pharmacological activation of Kv7 channels is an effective way to reduce neuronal firing. Our results showed that that pharmacologically activating the Kv7 channel with Retigabine (RTG) can alleviate cognitive impairment in mice without affecting spontaneous activity. RTG could also ameliorate damage to the Nissl bodies in cortex and hippocampal CA and DG regions in 9-month-old APP/PS1 mice. Additionally, RTG could reduce the Aβ plaque number in the hippocampus and cortex of both 6-month-old and 9-month-old mice. By recordings of electroencephalogram, we showed that a decrease in the number of abnormal discharges in the brains of the AD model mice when the Kv7 channel was opened. Moreover, Western blot analysis revealed a reduction in the expression of the p-Tau protein in both the hippocampus and cortex upon Kv7 channel opening. These findings suggest that Kv7 channel opener RTG may ameliorate cognitive impairment in AD, most likely by reducing brain excitability.

Oral pre- and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice.

Cannabis consumption has increased from 1.5% to 2.5% in Canada between 2012 and 2019. Clinical studies have indicated effects of prenatal cannabis exposure on birth weight, substance use, and neurodevelopmental disorders, but are confounded by several difficult to control variables. Animal models allow for examination of the mechanism of cannabis-induced changes in neurodevelopment and behavior, while controlling dose and timing. Several animal models of prenatal cannabis exposure exist which provide varying levels of construct validity, control of dose, and exposure to maternal stress. Using a voluntary oral consumption model, mouse dams received 5 mg/kg Δ9-tetrahydrocannabinol (THC) whole cannabis oil in peanut butter daily from gestational day 1 (GD1) to postnatal day 10 (PD10). At GD1, GD18, PD1, PD10, and PD15, maternal plasma was collected; pup brains were collected from GD18 onward. Pup brains had higher levels of THC and cannabidiol at each time point, each of which persisted in maternal plasma and pup brains past the end of treatment (PD15). Male and female adolescent offspring were examined for changes to ventral tegmental area (VTA) dopamine neuron activity and cocaine-seeking behavior. Prenatal and early postnatal (GD1-PD10) cannabis-exposed male, but not female mice had decreased gamma-aminobutyric acid (GABAergic) input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons. Cannabis-exposed offspring showed faster decay of N-methyl-D-aspartate (NMDA) currents in both sexes. However, no differences in cocaine-seeking behavior were noted. These data characterize a voluntary prenatal cannabis exposure model and demonstrates VTA dopamine neuronal activity is disinhibited in offspring.

Dissecting attention: Rate modulation vs. phase locking

In this issue of Neuron, Spyropoulos etal.1 report direct top-down modulation of neuronal firing rates underlying selective visual attentional modulation.

Impact of Unitary Synaptic Inhibition on Spike Timing in Ventral Tegmental Area Dopamine Neurons.

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus and ventral pallidum afferents. We next determined the phase resetting curve, the reversal potential for GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs), and the average interspike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the interspike interval or phase. Simulations were performed to predict the pause duration resulting from the synchronous arrival of multiple uIPSGs and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns, including pauses that have been implicated in reinforcement.

Microglial MyD88-dependent pathways are regulated in a sex-specific manner in the context of HMGB1-induced anxiety.

Chronic stress is a significant risk factor for the development and recurrence of anxiety disorders. Chronic stress impacts the immune system, causing microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is an established modulator of neuronal firing and a potent pro-inflammatory stimulus released from neuronal and non-neuronal cells following stress. HMGB1, in the context of stress, acts as a danger-associated molecular pattern (DAMP), instigating robust proinflammatory responses throughout the brain, so much so that localized drug delivery of HMGB1 alters behavior in the absence of any other forms of stress, i.e., social isolation, or behavioral stress models. Few studies have investigated the molecular mechanisms that underlie HMGB1-associated behavioral effects in a cell-specific manner. The aim of this study is to investigate cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction with regard to cell-type specificity and potential sex differences. Here, we report that both male and female mice exhibited anxiety-like behavior following increased HMGB1 in the mPFC as well as changes in microglial morphology. Interestingly, our results demonstrate that HMGB1-induced anxiety may be mediated by distinct microglial MyD88-dependent mechanisms in females compared to males. This study supports the hypothesis that MyD88 signaling in microglia may be a crucial mediator of the stress response in adult female mice.

Nav1.2 channel mutations preventing fast inactivation lead to SCN2A encephalopathy

Abstract SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations affecting the fast inactivation gating mechanism can result in altered voltage dependence and incomplete inactivation of the encoded neuronal Nav1.2 channel and lead to abnormal neuronal excitability. In this study, we evaluated clinical data of seven missense Nav1.2 variants associated with DEE and performed molecular dynamics simulations, patch-clamp electrophysiology, and dynamic clamp real-time neuronal modelling to elucidate the molecular and neuron-scale phenotypic consequences of the mutations. The N1662D mutation almost completely prevented fast inactivation without affecting activation. The comparison of wild-type and N1662D channel structures suggested that the ambifunctional hydrogen bond formation between residues N1662 and Q1494 is essential for fast inactivation. Fast inactivation could also be prevented with engineered Q1494A or Q1494L Nav1.2 channel variants, whereas Q1494E or Q1494 K variants resulted in incomplete inactivation and persistent current. Molecular dynamics simulations revealed a reduced affinity of the hydrophobic IFM-motif to its receptor site with N1662D and Q1494L variants relative to wild-type. These results demonstrate that the interactions between N1662 and Q1494 underpin the stability and the orientation of the inactivation gate and are essential for the development of fast inactivation. Six DEE-associated Nav1.2 variants, with mutations mapped to channel segments known to be implicated in fast inactivation were also evaluated. Remarkably, the L1657P variant also prevented fast inactivation and produced biophysical characteristics that were similar to those of N1662D, whereas the M1501 V, M1501T, F1651C, P1658S, and A1659 V variants resulted in biophysical properties that were consistent with gain-of-function and enhanced action potential firing of hybrid neurons in dynamic action potential clamp experiments. Paradoxically, low densities of N1662D or L1657P currents potentiated action potential firing, whereas increased densities resulted in sustained depolarization. Our results provide novel structural insights into the molecular mechanism of Nav1.2 channel fast inactivation and inform treatment strategies for SCN2A-related EI-DEE. The contribution of non-inactivating Nav1.2 channels to neuronal excitability may constitute a distinct cellular mechanism in the pathogenesis of SCN2A-related DEE.

Timescales of learning in prefrontal cortex.

The lateral prefrontal cortex (PFC) in humans and other primates is critical for immediate, goal-directed behaviour and working memory, which are classically considered distinct from the cognitive and neural circuits that support long-term learning and memory. Over the past few years, a reconsideration of this textbook perspective has emerged, in that different timescales of memory-guided behaviour are in constant interaction during the pursuit of immediate goals. Here, we will first detail how neural activity related to the shortest timescales of goal-directed behaviour (which requires maintenance of current states and goals in working memory) is sculpted by long-term knowledge and learning - that is, how the past informs present behaviour. Then, we will outline how learning across different timescales (from seconds to years) drives plasticity in the primate lateral PFC, from single neuron firing rates to mesoscale neuroimaging activity patterns. Finally, we will review how, over days and months of learning, dense local and long-range connectivity patterns in PFC facilitate longer-lasting changes in population activity by changing synaptic weights and recruiting additional neural resources to inform future behaviour. Our Review sheds light on how the machinery of plasticity in PFC circuits facilitates the integration of learned experiences across time to best guide adaptive behaviour.

The effects of morphine administration on the central nervous system (CNS): advantages and disadvantages

Morphine, a potent opioid analgesic, plays a critical role in pain management but elicits complex effects on the central nervous system (CNS), demonstrating both beneficial and detrimental outcomes. This paper reviews preclinical studies to examine morphine's interactions with the CNS, notably via binding to opioid receptors, leading to analgesia as well as a series of adverse effects, including addiction, tolerance, and neurological impairments. Acute exposure to morphine alters neurotransmitter activity, gene expression, and neuronal firing rates. In contrast, chronic use results in significant neuronal damage, altered memory functions, increased pain sensitivity, and neuroinflammation, highlighting the drug's impact on neurogenesis and neural cell viability. Additionally, morphine's protective properties against neurotoxic insults are discussed, alongside its potential to disrupt cellular and molecular pathways, culminating in neurotoxicity and cognitive deficits. Given the dual nature of morphine's impact on the CNS - protective vs. harmful, depending on specific conditions such as dosage, disease type, and administration frequency - this paper underscores the necessity for further research to untangle this complex interplay to leverage morphine's pain management benefits while minimizing its risks. A thorough evaluation of morphine administration practices can help reconcile these conflicting results.

Differences in the consolidation by spontaneous and evoked ripples in the presence of active dendrites.

Ripples are a typical form of neural activity in hippocampal neural networks associated with the replay of episodic memories during sleep as well as sleep-related plasticity and memory consolidation. The emergence of ripples has been observed both dependent as well as independent of input from other brain areas and often coincides with dendritic spikes. Yet, it is unclear how input-evoked and spontaneous ripples as well as dendritic excitability affect plasticity and consolidation. Here, we use mathematical modeling to compare these cases. We find that consolidation as well as the emergence of spontaneous ripples depends on a reliable propagation of activity in feed-forward structures which constitute memory representations. This propagation is facilitated by excitable dendrites, which entail that a few strong synapses are sufficient to trigger neuronal firing. In this situation, stimulation-evoked ripples lead to the potentiation of weak synapses within the feed-forward structure and, thus, to a consolidation of a more general sequence memory. However, spontaneous ripples that occur without stimulation, only consolidate a sparse backbone of the existing strong feed-forward structure. Based on this, we test a recently hypothesized scenario in which the excitability of dendrites is transiently enhanced after learning, and show that such a transient increase can strengthen, restructure and consolidate even weak hippocampal memories, which would be forgotten otherwise. Hence, a transient increase in dendritic excitability would indeed provide a mechanism for stabilizing memories.