Phototransduction in Drosophila is mediated by phospholipase C (PLC) and Ca²⁺-permeable TRP channels, but the function of endoplasmic reticulum (ER) Ca²⁺ stores in this important model for Ca²⁺ signaling remains obscure. We therefore expressed a low affinity Ca²⁺ indicator (ER-GCaMP6-150) in the ER, and measured its fluorescence both in dissociated ommatidia and in vivo from intact flies of both sexes. Blue excitation light induced a rapid (tau ~0.8 s), PLC-dependent decrease in fluorescence, representing depletion of ER Ca²⁺ stores, followed by a slower decay, typically reaching ~50% of initial dark-adapted levels, with significant depletion occurring under natural levels of illumination. The ER stores refilled in the dark within 100–200 s. Both rapid and slow store depletion were largely unaffected in InsP₃ receptor mutants, but were much reduced in trp mutants. Strikingly, rapid (but not slow) depletion of ER stores was blocked by removing external Na⁺ and in mutants of the Na⁺/Ca²⁺ exchanger, CalX, which we immuno-localized to ER membranes in addition to its established localization in the plasma membrane. Conversely, overexpression of calx greatly enhanced rapid depletion. These results indicate that rapid store depletion is mediated by Na⁺/Ca²⁺ exchange across the ER membrane induced by Na⁺ influx via the light-sensitive channels. Although too slow to be involved in channel activation, this Na⁺/Ca²⁺ exchange-dependent release explains the decades-old observation of a light-induced rise in cytosolic Ca²⁺ in photoreceptors exposed to Ca²⁺-free solutions.

SIGNIFICANCE STATEMENT Phototransduction in Drosophila is mediated by phospholipase C, which activates TRP cation channels by an unknown mechanism. Despite much speculation, it is unknown whether endoplasmic reticulum (ER) Ca²⁺ stores play any role. We therefore engineered flies expressing a genetically encoded Ca²⁺ indicator in the photoreceptor ER. Although NCX Na⁺/Ca²⁺ exchangers are classically believed to operate only at the plasma membrane, we demonstrate a rapid light-induced depletion of ER Ca²⁺ stores mediated by Na⁺/Ca²⁺ exchange across the ER membrane. This NCX-dependent release was too slow to be involved in channel activation, but explains the decades-old observation of a light-induced rise in cytosolic Ca²⁺ in photoreceptors bathed in Ca²⁺-free solutions.

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [¹¹C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[¹¹C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[¹¹C]ABP688 and [¹¹C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

Pattern separation and completion are fundamental hippocampal computations supporting memory encoding and retrieval. However, despite extensive exploration of these processes, it remains unclear whether and how top-down processes adaptively modulate the dynamics between these computations. Here we examine the role of expectation in shifting the hippocampus to perform pattern separation. In a behavioral task, 29 participants (7 males) learned a cue-object category contingency. Then, at encoding, one-third of the cues preceding the to-be-memorized objects, violated the studied rule. At test, participants performed a recognition task with old objects (targets) and a set of parametrically manipulated (very similar to dissimilar) foils for each object. Accuracy was found to be better for foils of high similarity to targets that were contextually unexpected at encoding compared with expected ones. Critically, there were no expectation-driven differences for targets and low similarity foils. To further explore these effects, we implemented a computational model of the hippocampus, performing the same task as the human participants. We used representational similarity analysis to examine how top-down expectation interacts with bottom-up perceptual input, in each layer. All subfields showed more dissimilar representations for unexpected items, with dentate gyrus (DG) and CA3 being more sensitive to expectation violation than CA1. Again, representational differences between expected and unexpected inputs were prominent for moderate to high levels of input similarity. This effect diminished when inputs from DG and CA3 into CA1 were lesioned. Overall, these novel findings strongly suggest that pattern separation in DG/CA3 underlies the effect that violation of expectation exerts on memory.

SIGNIFICANCE STATEMENT What makes some events more memorable than others is a key question in cognitive neuroscience. Violation of expectation often leads to better memory performance, but the neural mechanism underlying this benefit remains elusive. In a behavioral study, we found that memory accuracy is enhanced selectively for unexpected highly similar foils, suggesting expectation violation does not enhance memory indiscriminately, but specifically aids the disambiguation of overlapping inputs. This is further supported by our subsequent investigation using a hippocampal computational model, revealing increased representational dissimilarity for unexpected highly similar foils in DG and CA3. These convergent results provide the first evidence that pattern separation plays an explicit role in supporting memory for unexpected information.

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.

SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

Priming refers to the influence that a previously encountered object exerts on future responses to similar objects. For many years, visual priming has been known as a facilitation and sometimes an inhibition effect that lasts for an extended period of time. It contrasts with the recent finding of an oscillated priming effect where facilitation and inhibition alternate over time periodically. Here we developed a computational model of visual priming that combines rhythmic sampling of the environment (attentional oscillation) with active preparation for future events (temporal expectation). Counterintuitively, it shows that both the sustained and oscillated priming effects can emerge from an interaction between attentional oscillation and temporal expectation. The interaction also leads to novel predictions, such as the change of visual priming effects with temporal expectation and attentional oscillation. Reanalysis of two published datasets and the results of two new experiments of visual priming tasks with male and female human participants provide support for the model's relevance to human behavior. More generally, our model offers a new perspective that may unify the increasing findings of behavioral and neural oscillations with the classic findings in visual perception and attention.

SIGNIFICANCE STATEMENT There is increasing behavioral and neural evidence that visual attention is a periodic process that sequentially samples different alternatives in the theta frequency range. It contrasts with the classic findings of sustained facilitatory or inhibitory attention effects. How can an oscillatory perceptual process give rise to sustained attention effects? Here we make this connection by proposing a computational model for a "fruit fly" visual priming task and showing both the sustained and oscillated priming effects can have the same origin: an interaction between rhythmic sampling of the environment and active preparation for future events. One unique contribution of our model is to predict how temporal contexts affects priming. It also opens up the possibility of reinterpreting other attention-related classic phenomena.

For visually guided navigation, the use of environmental cues is essential. Particularly, detecting local boundaries that impose limits to locomotion and estimating their location is crucial. In a series of three fMRI experiments, we investigated whether there is a neural coding of navigational distance in the human visual cortex (both female and male). We used virtual reality software to systematically manipulate the distance from a viewer perspective to different types of a boundary. Using a multivoxel pattern classification employing a linear support vector machine, we found that the occipital place area (OPA) is sensitive to the navigational distance restricted by the transparent glass wall. Further, the OPA was sensitive to a non-crossable boundary only, suggesting an importance of the functional constraint of a boundary. Together, we propose the OPA as a perceptual source of external environmental features relevant for navigation.

SIGNIFICANCE STATEMENT One of major goals in cognitive neuroscience has been to understand the nature of visual scene representation in human ventral visual cortex. An aspect of scene perception that has been overlooked despite its ecological importance is the analysis of space for navigation. One of critical computation necessary for navigation is coding of distance to environmental boundaries that impose limit on navigator's movements. This paper reports the first empirical evidence for coding of navigational distance in the human visual cortex and its striking sensitivity to functional constraint of environmental boundaries. Such finding links the paper to previous neurological and behavioral works that emphasized the distance to boundaries as a crucial geometric property for reorientation behavior of children and other animal species.

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM⁺) interneurons, in mice of both sexes. We found that inactivating SOM⁺ cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM⁺ cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features.

SIGNIFICANCE STATEMENT To generate coherent percepts, sensory systems integrate simultaneously occurring features of a stimulus, yet the mechanisms by which this integration occurs are not fully understood. Our results show that neurochemically distinct neuronal subtypes in the primary auditory cortex have different contributions to the integration of different frequency components of an acoustic stimulus. Together with findings from other sensory cortices, our results provide evidence of a common mechanism for cortical computations used for global integration of stimulus features.

Neonatal stroke is as frequent as stroke in the elderly, but many pathophysiological injury aspects are distinct in neonates, including immune signaling. While myeloid cells can traffic into the brain via multiple routes, the choroid plexus (CP) has been identified as a uniquely educated gate for immune cell traffic during health and disease. To understand the mechanisms of myeloid cell trafficking via the CP and their influence on neonatal stroke, we characterized the phenotypes of CP-infiltrating myeloid cells after transient middle cerebral artery occlusion (tMCAO) in neonatal mice of both sexes in relation to blood-brain barrier permeability, injury, microglial activation, and CX3CR1-CCR2 signaling, focusing on the dynamics early after reperfusion. We demonstrate rapid recruitment of multiple myeloid phenotypes in the CP ipsilateral to the injury, including inflammatory CD45⁺CD11b⁺Ly6c^highCD86⁺, beneficial CD45⁺CD11b⁺Ly6c^lowCD206⁺, and CD45⁺CD11b⁺Ly6c^lowLy6g^high cells, but only minor leukocyte infiltration into acutely ischemic-reperfused cortex and negligible vascular albumin leakage. We report that CX3CR1-CCR2-mediated myeloid cell recruitment contributes to stroke injury. Considering the complexity of inflammatory cascades triggered by stroke and a role for TLR2 in injury, we also used direct TLR2 stimulation as an independent injury model. TLR2 agonist rapidly recruited myeloid cells to the CP, increased leukocytosis in the CSF and blood, but infiltration into the cortex remained low over time. While the magnitude and the phenotypes of myeloid cells diverged between tMCAO and TLR2 stimulation, in both models, disruption of CX3CR1-CCR2 signaling attenuated both monocyte and neutrophil trafficking to the CP and cortex.

SIGNIFICANCE STATEMENT Stroke during the neonatal period leads to long-term disabilities. The mechanisms of ischemic injury and inflammatory response differ greatly between the immature and adult brain. We examined leukocyte trafficking via the choroid plexus (CP) following neonatal stroke in relation to blood-brain barrier integrity, injury, microglial activation, and signaling via CX3CR1 and CCR2 receptors, or following direct TLR2 stimulation. Ischemia-reperfusion triggered marked unilateral CX3CR1-CCR2 dependent accumulation of diverse leukocyte subpopulations in the CP without inducing extravascular albumin leakage or major leukocyte infiltration into the brain. Disrupted CX3CR1-CCR2 signaling was neuroprotective in part by attenuating monocyte and neutrophil trafficking. Understanding the migratory patterns of CP-infiltrating myeloid cells with intact and disrupted CX3CR1-CCR2 signaling could identify novel therapeutic targets to protect the neonatal brain.

Investment of cognitive effort is required in everyday life and has received ample attention in recent neurocognitive frameworks. The neural mechanism of effort investment is thought to be structured hierarchically, with dorsal anterior cingulate cortex (dACC) at the highest level, recruiting task-specific upstream areas. In the current fMRI study, we tested whether dACC is generally active when effort demand is high across tasks with different stimuli, and whether connectivity between dACC and task-specific areas is increased depending on the task requirements and effort level at hand. For that purpose, a perceptual detection task was administered that required male and female human participants to detect either a face or a house in a noisy image. Effort demand was manipulated by adding little (low effort) or much (high effort) noise to the images. Results showed a network of dACC, anterior insula (AI), and intraparietal sulcus (IPS) to be more active when effort demand was high, independent of the performed task (face or house detection). Importantly, effort demand modulated functional connectivity between dACC and face-responsive or house-responsive perceptual areas, depending on the task at hand. This shows that dACC, AI, and IPS constitute a general effort-responsive network and suggests that the neural implementation of cognitive effort involves dACC-initiated sensitization of task-relevant areas.

SIGNIFICANCE STATEMENT Although cognitive effort is generally perceived as aversive, its investment is inevitable when navigating an increasingly complex society. In this study, we demonstrate how the human brain tailors the implementation of effort to the requirements of the task at hand. We show increased effort-related activity in a network of brain areas consisting of dorsal anterior cingulate cortex (dACC), anterior insula, and intraparietal sulcus, independent of task specifics. Crucially, we also show that effort-induced functional connectivity between dACC and task-relevant areas tracks specific task demands. These results demonstrate how brain regions specialized to solve a task may be energized by dACC when effort demand is high.

Statistical regularities in natural sounds facilitate the perceptual segregation of auditory sources, or streams. Repetition is one cue that drives stream segregation in humans, but the neural basis of this perceptual phenomenon remains unknown. We demonstrated a similar perceptual ability in animals by training ferrets of both sexes to detect a stream of repeating noise samples (foreground) embedded in a stream of random samples (background). During passive listening, we recorded neural activity in primary auditory cortex (A1) and secondary auditory cortex (posterior ectosylvian gyrus, PEG). We used two context-dependent encoding models to test for evidence of streaming of the repeating stimulus. The first was based on average evoked activity per noise sample and the second on the spectro-temporal receptive field. Both approaches tested whether differences in neural responses to repeating versus random stimuli were better modeled by scaling the response to both streams equally (global gain) or by separately scaling the response to the foreground versus background stream (stream-specific gain). Consistent with previous observations of adaptation, we found an overall reduction in global gain when the stimulus began to repeat. However, when we measured stream-specific changes in gain, responses to the foreground were enhanced relative to the background. This enhancement was stronger in PEG than A1. In A1, enhancement was strongest in units with low sparseness (i.e., broad sensory tuning) and with tuning selective for the repeated sample. Enhancement of responses to the foreground relative to the background provides evidence for stream segregation that emerges in A1 and is refined in PEG.

SIGNIFICANCE STATEMENT To interact with the world successfully, the brain must parse behaviorally important information from a complex sensory environment. Complex mixtures of sounds often arrive at the ears simultaneously or in close succession, yet they are effortlessly segregated into distinct perceptual sources. This process breaks down in hearing-impaired individuals and speech recognition devices. By identifying the underlying neural mechanisms that facilitate perceptual segregation, we can develop strategies for ameliorating hearing loss and improving speech recognition technology in the presence of background noise. Here, we present evidence to support a hierarchical process, present in primary auditory cortex and refined in secondary auditory cortex, in which sound repetition facilitates segregation.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Na_v1.6 and K_v7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (~2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.

SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.

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