publications
the full list of the lab's publications!
2023
- </li>Excessive proteostasis contributes to pathology in fragile X syndromeSusana R. Louros , Sang S. Seo , Beatriz Maio , and 8 more authorsFeb 2023
In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1-/y) neurons. Surprisingly, although we find a significant increase in protein degra-dation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1-/y mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1-/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention.
</li></ol>Memory consolidation: Building influence over the entorhinal cortexMatthew F. NolanNov 2023Memory consolidation involves interactions between the hippocampus and other cortical areas. A new study identifies neurons in the medial entorhinal cortex that over learning increase their coordination with hippocampal replay events, suggesting a route for consolidation of spatial memories.
2022
- </li>Single Photon Kilohertz Frame Rate Imaging of Neural ActivityTian Tian , Yifang Yuan , Srinjoy Mitra , and 2 more authorsNov 2022
Establishing the biological basis of cognition and its disorders will require high precision spatiotemporal measurements of neural activity. Recently developed genetically encoded voltage indicators (GEVIs) report both spiking and subthreshold activity of identified neurons. However, maximally capitalizing on the potential of GEVIs will require imaging at millisecond time scales, which remains challenging with standard camera systems. Here, application of single photon avalanche diode (SPAD) sensors is reported to image neural activity at kilohertz frame rates. SPADs are electronic devices that when activated by a single photon cause an avalanche of electrons and a large electric current. An array of SPAD sensors is used to image individual neurons expressing the GEVI Voltron-JF525-HTL. It is shown that subthreshold and spiking activity can be resolved with shot noise limited signals at frame rates of up to 10 kHz. SPAD imaging is able to reveal millisecond scale synchronization of neural activity in an ex vivo seizure model. SPAD sensors may have widespread applications for investigation of millisecond timescale neural dynamics.
</li>Spatial representation by ramping activity of neurons in the retrohippocampal cortexSarah A. Tennant , Harry Clark , Ian Hawes , and 6 more authorsOct 2022Neurons in the retrohippocampal cortices play crucial roles in spatial memory. Many retrohippocampal neu-rons have firing fields that are selectively active at specific locations, with memory for rewarded locations associated with reorganization of these firing fields. Whether this is the sole strategy for representing spatial memories is unclear. Here, we demonstrate that during a spatial memory task retrohippocampal neurons encode location through ramping activity that extends across segments of a linear track approaching and following a reward, with the rewarded location represented by offsets or switches in the slope of the ramping activity. Ramping representations could be maintained independently of trial outcome and cues marking the reward location, indicating that they result from recall of the track structure. When recorded in an open arena, neurons that generated ramping activity during the spatial memory task were more numerous than grid or border cells, with a majority showing spatial firing that did not meet criteria for classification as grid or border representations. Encoding of rewarded locations through offsets and switches in the slope of ramping activ-ity also emerged in recurrent neural network models trained to solve a similar spatial memory task. Impaired performance of model networks following disruption of outputs from ramping neurons is consistent with this coding strategy supporting navigation to recalled locations of behavioral significance. Our results suggest that encoding of learned spaces by retrohippocampal networks employs both discrete firing fields and continuous ramping representations. We hypothesize that retrohippocampal ramping activity mediates readout of learned models for goal-directed navigation.
</li>Fan cells in lateral entorhinal cortex directly influence medial entorhinal cortex through synaptic connections in layer 1Brianna Vandrey , Jack Armstrong , Christina M. Brown , and 2 more authorsDec 2022Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that, in mice, fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of inputs from fan cells evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABA(A) and GABA(B) receptors, respectively. Inputs from fan cells also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of ‘what’ and ‘where’ components of episodic memories.
</li></ol>pyNeurode: a real-time neural signal processing frameworkWing-Kin Tam , and Matthew F. NolanDec 2022IEEE International Symposium on Circuits and Systems (ISCAS), Austin, TX, MAY 28-JUN 01, 2022Accurate decoding of neural signals often requires assigning extracellular waveforms acquired on the same electrode to their originating neurons, a process known as spike sorting. While many offline sorters are available, accurate online sorting of spikes with many channels is still a challenging problem. Existing online sorters either use simple algorithms with low accuracy, can only process a handful of channels, or depend on a complex runtime environment that is difficult to set up. We have developed a state-of-the-art online spike sorting platform in Python that enables large-scale, fully automatic real-time spike sorting and decoding on hundreds of channels. Our system is cross-platform and works seamlessly with the Open Ephys suite of open-source hardware and software widely used in many neuroscience laboratories worldwide. It also comes with a user-friendly graphical user interface to monitor the cluster quality, spike waveforms and neuronal firing rate. Our platform has comparable accuracy to offline sorters and can achieve an end-to-end sorting latency of around 160 ms for 128-channel signals. It will be useful for research in fundamental neuroscience, closed-loop feedback neuromodulation and brain-computer interfaces.
2021
- </li>Medial septal GABAergic neurons reduce seizure duration upon optogenetic closed-loop stimulationKaterina Hristova , Cristina Martinez-Gonzalez , Thomas C. Watson , and 5 more authorsMay 2021
Seizures can emerge from multiple or large foci in temporal lobe epilepsy, complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons, which provide extensive projections throughout the hippocampus, is used to control seizures. We utilized the chronic intrahippocampal kainate mouse model of temporal lobe epilepsy, which results in spontaneous seizures and as is often the case in human patients, presents with hippocampal sclerosis. Medial septal GABAergic neuron populations were immunohistochemically labelled and were not reduced in epileptic conditions. Genetic labelling with mRuby of medial septal GABAergic neuron synaptic puncta and imaging across the rostral to caudal extent of the hippocampus, also indicated an unchanged number of putative synapses in epilepsy. Furthermore, optogenetic stimulation of medial septal GABAergic neurons consistently modulated oscillations across multiple hippocampal locations in control and epileptic conditions. Finally, wireless optogenetic stimulation of medial septal GABAergic neurons, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose medial septal GABAergic neurons as a novel target for optogenetic control of seizures in temporal lobe epilepsy.
</li>NOLAN, SÜRMELIDeep entorhinal cortex: from circuit organization to spatial cognition and memoryKlara Z. Gerlei , Christina M. Brown , Gulsen Surmeli , and 1 more authorNov 2021The deep layers of the entorhinal cortex are important for spatial cognition, as well as memory storage, consolidation and retrieval. A long-standing hypothesis is that deep-layer neurons relay spatial and memory-related signals between the hippocampus and telencephalon. We review the implications of recent circuit-level analyses that suggest more complex roles. The organization of deep entorhinal layers is consistent with multi-stage processing by specialized cell populations; in this framework, hippocampal, neocortical, and subcortical inputs are integrated to generate representations for use by targets in the telencephalon and for feedback to the superficial entorhinal cortex and hippocampus. Addressing individual sublayers of the deep entorhinal cortex in future experiments and models will be important for establishing systems-level mechanisms for spatial cognition and episodic memory.
</li></ol>Medial septal GABAergic neurons reduce seizure duration upon optogenetic closed-loop stimulation (vol 144, pg 1576, 2021)Katerina Hristova , Cristina Martinez-Gonzalez , Thomas C. Watson , and 5 more authorsSep 20212020
- </li>Fan Cells in Layer 2 of the Lateral Entorhinal Cortex Are Critical for Episodic-like MemoryBrianna Vandrey , Derek L. F. Garden , Veronika Ambrozova , and 3 more authorsJan 2020
Episodic memory requires different types of information to be bound together to generate representations of experiences. The lateral entorhinal cortex (LEC) and hippocampus are required for episodic like memory in rodents [1, 2]. The LEC is critical for integrating spatial and contextual information about objects [236]. Further, LEC neurons encode objects in the environment and the locations where objects were previously experienced and generate representations of time during the encoding and retrieval of episodes [7312]. However, it remains unclear how specific populations of cells within the LEC contribute to the integration of episodic memory components. Layer 2 (L2) of LEC manifests early pathology in Alzheimer’s disease (AD) and related animal models [13-16]. Projections to the hippocampus from L2 of LEC arise from fan cells in a superficial sub -layer (L2a) that are immunoreactive for reelin and project to the dentate gyrus [17, 18]. Here, we establish an approach for selectively targeting fan cells using Siml:Cre mice. Whereas complete lesions of the LEC were previously found to abolish associative recognition memory [2, 3], we report that, after selective suppression of synaptic output from fan cells, mice can discriminate novel object-context configurations but are impaired in recognition of novel object-place-context associations. Our results suggest that memory functions are segregated between distinct LEC networks.
</li>Inter- and intra-animal variation in the integrative properties of stellate cells in the medial entorhinal cortexHugh Pastoll , Derek L. Garden , Ioannis Papastathopoulos , and 2 more authorsFeb 2020Distinctions between cell types underpin organizational principles for nervous system function. Functional variation also exists between neurons of the same type. This is exemplified by correspondence between grid cell spatial scales and the synaptic integrative properties of stellate cells (SCs) in the medial entorhinal cortex. However, we know little about how functional variability is structured either within or between individuals. Using ex-vivo patch-clamp recordings from up to 55 SCs per mouse, we found that integrative properties vary between mice and, in contrast to the modularity of grid cell spatial scales, have a continuous dorsoventral organization. Our results constrain mechanisms for modular grid firing and provide evidence for inter-animal phenotypic variability among neurons of the same type. We suggest that neuron type properties are tuned to circuit-level set points that vary within and between animals.
</li></ol>Grid cells are modulated by local head directionKlara Gerlei , Jessica Passlack , Ian Hawes , and 4 more authorsAug 2020Grid and head direction codes represent cognitive spaces for navigation and memory. Pure grid cells generate grid codes that have been assumed to be independent of head direction, whereas conjunctive cells generate grid representations that are tuned to a single head direction. Here, we demonstrate that pure grid cells also encode head direction, but through distinct mechanisms. We show that individual firing fields of pure grid cells are tuned to multiple head directions, with the preferred sets of directions differing between fields. This local directional modulation is not predicted by previous continuous attractor or oscillatory interference models of grid firing but is accounted for by models in which pure grid cells integrate inputs from co-aligned conjunctive cells with firing rates that differ between their fields. We suggest that local directional signals from grid cells may contribute to downstream computations by decorrelating different points of view from the same location. Neurons with grid firing fields are thought to play important roles in spatial cognition. Here, the authors show that in contrast to assumptions underlying current models and analyses, grid fields are modulated by local head direction; this suggests different mechanisms and new roles for grid firing.
2018
- </li>Stellate Cells in the Medial Entorhinal Cortex Are Required for Spatial LearningSarah A. Tennant , Lukas Fischer , Derek L. F. Garden , and 5 more authorsJan 2018
Spatial learning requires estimates of location that may be obtained by path integration or from positional cues. Grid and other spatial firing patterns of neurons in the superficial medial entorhinal cortex (MEC) suggest roles in behavioral estimation of location. However, distinguishing the contributions of path integration and cue-based signals to spatial behaviors is challenging, and the roles of identified MEC neurons are unclear. We use virtual reality to dissociate linear path integration from other strategies for behavioral estimation of location. We find that mice learn to path integrate using motor-related self-motion signals, with accuracy that decreases steeply as a function of distance. We show that inactivation of stellate cells in superficial MEC impairs spatial learning in virtual reality and in a real world object location recognition task. Our results quantify contributions of path integration to behavior and corroborate key predictions of models in which stellate cells contribute to location estimation.
</li></ol>Inferior Olive HCN1 Channels Coordinate Synaptic Integration and Complex Spike TimingDerek L. F. Garden , Marlies Oostland , Marta Jelitai , and 3 more authorsFeb 2018Cerebellar climbing-fiber-mediated complex spikes originate from neurons in the inferior olive (IO), are critical for motor coordination, and are central to theories of cerebellar learning. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels expressed by IO neurons have been considered as pacemaker currents important for oscillatory and resonant dynamics. Here, we demonstrate that in vitro, network actions of HCN1 channels enable bidirectional glutamatergic synaptic responses, while local actions of HCN1 channels determine the timing and waveform of synaptically driven action potentials. These roles are distinct from, and may complement, proposed pacemaker functions of HCN channels. We find that in behaving animals HCN1 channels reduce variability in the timing of cerebellar complex spikes, which serve as a readout of IO spiking. Our results suggest that spatially distributed actions of HCN1 channels enable the IO to implement network-wide rules for synaptic integration that modulate the timing of cerebellar climbing fiber signals.
2017
- </li>Grid cells’ need for speedAlfredo Gonzalez-Sulser , and Matthew F. NolanJan 2017
Grid-firing fields of neurons in the entorhinal cortex are thought to require inputs encoding running speed. Glutamatergic projections from the medial septum may be one of the inputs that provide these speed signals.
</li>Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentialsDerek L. F. Garden , Arianna Rinaldi , and Matthew F. NolanFeb 2017The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long-range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABA(A) independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium-activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium-activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals 20ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours.
</li></ol>Synaptic integrative mechanisms for spatial cognitionChristoph Schmidt-Hieber , and Matthew F. NolanNov 2017Synaptic integrative mechanisms have profound effects on electrical signaling in the brain that, although largely hidden from recording methods that observe the spiking activity of neurons, may be critical for the encoding, storage and retrieval of information. Here we review roles for synaptic integrative mechanisms in the selection, generation and plasticity of place and grid fields, and in related temporal codes for the representation of space. We outline outstanding questions and challenges in the testing of hypothesized models for spatial computation and memory.
2016
- </li>Local field potentials get funnyMatthew F. NolanJul 2016</li>NOLAN, SÜRMELIMolecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex (vol 88, pg 1040, 2015)Gulsen Surmeli , Daniel Cosmin Marcu , Christina McClure , and 3 more authorsNov 2016</li>Neural mechanisms for spatial computationMatthew F. NolanNov 2016</li>Continuous attractor network models of grid cell firing based on excitatory-inhibitory interactionsOliver Shipston-Sharman , Lukas Solanka , and Matthew F. NolanNov 2016
Neurons in the medial entorhinal cortex encode location through spatial firing fields that have a grid-like organisation. The challenge of identifying mechanisms for grid firing has been addressed through experimental and theoretical investigations of medial entorhinal circuits. Here, we discuss evidence for continuous attractor network models that account for grid firing by synaptic interactions between excitatory and inhibitory cells. These models assume that grid-like firing patterns are the result of computation of location from velocity inputs, with additional spatial input required to oppose drift in the attractor state. We focus on properties of continuous attractor networks that are revealed by explicitly considering excitatory and inhibitory neurons, their connectivity and their membrane potential dynamics. Models at this level of detail can account for theta-nested gamma oscillations as well as grid firing, predict spatial firing of interneurons as well as excitatory cells, show how gamma oscillations can bemodulated independently from spatial computations, reveal critical roles for neuronal noise, and demonstrate that only a subset of excitatory cells in a network need have grid-like firing fields. Evaluating experimental data against predictions from detailed network models will be important for establishing the mechanisms mediating grid firing.
</li></ol>Flexible theta sequence compression mediated via phase precessing interneuronsAngus Chadwick , Mark C. W. Rossum , and Matthew F. NolanDec 2016Encoding of behavioral episodes as spike sequences during hippocampal theta oscillations provides a neural substrate for computations on events extended across time and space. However, the mechanisms underlying the numerous and diverse experimentally observed properties of theta sequences remain poorly understood. Here we account for theta sequences using a novel model constrained by the septo-hippocampal circuitry. We show that when spontaneously active interneurons integrate spatial signals and theta frequency pacemaker inputs, they generate phase precessing action potentials that can coordinate theta sequences in place cell populations. We reveal novel constraints on sequence generation, predict cellular properties and neural dynamics that characterize sequence compression, identify circuit organization principles for high capacity sequential representation, and show that theta sequences can be used as substrates for association of conditioned stimuli with recent and upcoming events. Our results suggest mechanisms for flexible sequence compression that are suited to associative learning across an animals lifespan.
2015
- </li>Independent Theta Phase Coding Accounts for CA1 Population Sequences and Enables Flexible RemappingAngus Chadwick , Mark C. W. Rossum , and Matthew F. NolanFeb 2015
Hippocampal place cells encode an animal’s past, current and future location through sequences of action potentials generated within each cycle of the network theta rhythm. These sequential representations have been suggested to result from temporally coordinated synaptic interactions within and between cell assemblies. Instead, we find through simulations and analysis of experimental data that rate and phase coding in independent neurons is sufficient to explain the organization of CA1 population activity during theta states. We show that CA1 population activity can be described as an evolving traveling wave that exhibits phase coding, rate coding, spike sequences and that generates an emergent population theta rhythm. We identify measures of global remapping and intracellular theta dynamics as critical for distinguishing mechanisms for pacemaking and coordination of sequential population activity. Our analysis suggests that, unlike synaptically coupled assemblies, independent neurons flexibly generate sequential population activity within the duration of a single theta cycle.
</li>Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene ExpressionHelen L. Ramsden , Guelsen Suermeli , Steven G. McDonagh , and 1 more authorJan 2015Neural circuits in the medial entorhinal cortex (MEC) encode an animal’s position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion-and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuro-anatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations.
</li>Noise promotes independent control of gamma oscillations and grid firing within recurrent attractor networksLukas Solanka , Mark C. W. Rossum , and Matthew F. NolanJul 2015Neural computations underlying cognitive functions require calibration of the strength of excitatory and inhibitory synaptic connections and are associated with modulation of gamma frequency oscillations in network activity. However, principles relating gamma oscillations, synaptic strength and circuit computations are unclear. We address this in attractor network models that account for grid firing and theta-nested gamma oscillations in the medial entorhinal cortex. We show that moderate intrinsic noise massively increases the range of synaptic strengths supporting gamma oscillations and grid computation. With moderate noise, variation in excitatory or inhibitory synaptic strength tunes the amplitude and frequency of gamma activity without disrupting grid firing. This beneficial role for noise results from disruption of epileptic-like network states. Thus, moderate noise promotes independent control of multiplexed firing rate-and gamma-based computational mechanisms. Our results have implications for tuning of normal circuit function and for disorders associated with changes in gamma oscillations and synaptic strength.
</li></ol>NOLAN, SÜRMELIMolecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal CortexGulsen Surmeli , Daniel Cosmin Marcu , Christina McClure , and 3 more authorsDec 2015Deep layers of the medial entorhinal cortex are considered to relay signals from the hippocampus to other brain structures, but pathways for routing of signals to and from the deep layers are not well established. Delineating these pathways is important for a circuit level understanding of spatial cognition and memory. We find that neurons in layers 5a and 5b have distinct molecular identities, defined by the transcription factors Etv1 and Ctip2, and divergent targets, with extensive intratelencephalic projections originating in layer 5a, but not 5b. This segregation of outputs is mirrored by the organization of glutamatergic input from stellate cells in layer 2 and from the hippocampus, with both preferentially targeting layer 5b over 5a. Our results suggest a molecular and anatomical organization of input-output computations in deep layers of the MEC, reveal precise translaminar microcircuitry, and identify molecularly defined pathways for spatial signals to influence computation in deep layers.
2014
- </li>Increased intrinsic excitability of muscle vasoconstrictor preganglionic neurons may contribute to the elevated sympathetic activity in hypertensive ratsLinford J. B. Briant , Alexey O. Stalbovskiy , Matthew F. Nolan , and 2 more authorsDec 2014
Hypertension is associated with pathologically increased sympathetic drive to the vasculature. This has been attributed to increased excitatory drive to sympathetic preganglionic neurons (SPN) from brainstem cardiovascular control centers. However, there is also evidence supporting increased intrinsic excitability of SPN. To test this hypothesis, we made whole cell recordings of muscle vasoconstrictor-like (MVClike) SPN in the working-heart brainstem preparation of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. The MVClike SPN have a higher spontaneous firing frequency in the SH rat (3.85 +/- 0.4 vs. 2.44 +/- 0.4 Hz in WKY; P = 0.011) with greater respiratory modulation of their activity. The action potentials of SH SPN had smaller, shorter afterhyperpolarizations (AHPs) and showed diminished transient rectification indicating suppression of an A-type potassium conductance (I-A). We developed mathematical models of the SPN to establish if changes in their intrinsic properties in SH rats could account for their altered firing. Reduction of the maximal conductance density of I-A by 15-30% changed the excitability and output of the model from the WKY to a SH profile, with increased firing frequency, amplified respiratory modulation, and smaller AHPs. This change in output is predominantly a consequence of altered synaptic integration. Consistent with these in silico predictions, we found that intrathecal 4-aminopyridine (4-AP) increased sympathetic nerve activity, elevated perfusion pressure, and augmented Traube-Hering waves. Our findings indicate that I-A acts as a powerful filter on incoming synaptic drive to SPN and that its diminution in the SH rat is potentially sufficient to account for the increased sympathetic output underlying hypertension.
</li></ol>GABAergic Projections from the Medial Septum Selectively Inhibit Interneurons in the Medial Entorhinal CortexAlfredo Gonzalez-Sulser , Daniel Parthier , Antonio Candela , and 5 more authorsDec 2014The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MSneurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MSneurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25-60 Hz) and high (60-180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits.
2013
- </li>Feedback Inhibition Enables Theta-Nested Gamma Oscillations and Grid Firing FieldsHugh Pastoll , Lukas Solanka , Mark C. W. Rossum , and 1 more authorJan 2013
Cortical circuits are thought to multiplex firing rate codes with temporal codes that rely on oscillatory network activity, but the circuit mechanisms that combine these coding schemes are unclear. We establish with optogenetic activation of layer II of the medial entorhinal cortex that theta frequency drive to this circuit is sufficient to generate nested gamma frequency oscillations in synaptic activity. These nested gamma oscillations closely resemble activity during spatial exploration, are generated by local feedback inhibition without recurrent excitation, and have clock-like features suitable as reference signals for multiplexing temporal codes within rate-coded grid firing fields. In network models deduced from our data, feedback inhibition supports coexistence of theta-nested gamma oscillations with attractor states that generate grid firing fields. These results indicate that grid cells communicate primarily via inhibitory interneurons. This circuit mechanism enables multiplexing of oscillation-based temporal codes with rate-coded attractor states.
</li>Prefrontal Cortex HCN1 Channels Enable Intrinsic Persistent Neural Firing and Executive Memory FunctionSebastien J. Thuault , Gael Malleret , Christine M. Constantinople , and 9 more authorsAug 2013In many cortical neurons, HCN1 channels are the major contributors to I-h, the hyperpolarization-activated current, which regulates the intrinsic properties of neurons and shapes their integration of synaptic inputs, paces rhythmic activity, and regulates synaptic plasticity. Here, we examine the physiological role of I-h in deep layer pyramidal neurons in mouse prefrontal cortex (PFC), focusing on persistent activity, a form of sustained firing thought to be important for the behavioral function of the PFC during working memory tasks. We find that HCN1 contributes to the intrinsic persistent firing that is induced by a brief depolarizing current stimulus in the presence of muscarinic agonists. Deletion of HCN1 or acute pharmacological blockade of I-h decreases the fraction of neurons capable of generating persistent firing. The reduction in persistent firing is caused by the membrane hyperpolarization that results from the deletion of HCN1 or I-h blockade, rather than a specific role of the hyperpolarization-activated current in generating persistent activity. In vivo recordings show that deletion of HCN1 has no effect on up states, periods of enhanced synaptic network activity. Parallel behavioral studies demonstrate that HCN1 contributes to the PFC-dependent resolution of proactive interference during working memory. These results thus provide genetic evidence demonstrating the importance of HCN1 to intrinsic persistent firing and the behavioral output of the PFC. The causal role of intrinsic persistent firing in PFC-mediated behavior remains an open question.
</li></ol>HCN1 channels in cerebellar Purkinje cells promote late stages of learning and constrain synaptic inhibitionArianna Rinaldi , Cagla Defterali , Antoine Mialot , and 3 more authorsNov 2013Neural computations rely on ion channels that modify neuronal responses to synaptic inputs. While single cell recordings suggest diverse and neurone type-specific computational functions for HCN1 channels, their behavioural roles in any single neurone type are not clear. Using a battery of behavioural assays, including analysis of motor learning in vestibulo-ocular reflex and rotarod tests, we find that deletion of HCN1 channels from cerebellar Purkinje cells selectively impairs late stages of motor learning. Because deletion of HCN1 modifies only a subset of behaviours involving Purkinje cells, we asked whether the channel also has functional specificity at a cellular level. We find that HCN1 channels in cerebellar Purkinje cells reduce the duration of inhibitory synaptic responses but, in the absence of membrane hyperpolarization, do not affect responses to excitatory inputs. Our results indicate that manipulation of subthreshold computation in a single neurone type causes specific modifications to behaviour.
2012
- </li></ol>Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fieldsHugh Pastoll , Helen L. Ramsden , and Matthew F. NolanApr 2012
The medial entorhinal contex (MEC) is an increasingly important focus for investigation of mechanisms for spatial representation. Grid cells found in layer II of the MEC are likely to be stellate cells, which form a major projection to the dentate gyrus. Entorhinal stellate cells are distinguished by distinct intrinsic electrophysiological properties, but how these properties contribute to representation of space is not yet clear. Here, we review the ionic conductances, synaptic, and excitable properties of stellate cells, and examine thier implication for models of grid firing fields. We discuss why existing data are inconsistent with models of grid fields that require stellate cells to generate periodic oscillation. An alternate possibility is that the intrinsic electrophysiological properties of stellate cells are tuned specifically to control integration of synaptic input. We highlight recent evidence that the dorsal-ventra; organization of synaptic integraiton by stellate cells, through differences in currents mediated by HCN and leak potassium channels, influences the corresponding organization of grid fields. Because accurate cellular data will be important for distinguishing mechanisms for generation of grid fields, we introduce new date comparing properties measured with whole-cell and perforated patch-clamp recordings. We find that clustered patterns of action potential firing and the action potential after-hyperpolarization (AHP) are particularly sensitive to recording condition. Neverthless, with both methods, these properties, resting membrane properties and resonance follow a dorsal-ventral organization. Further investigation of the molecular basis for synaptic integration by stellate cells will be important for understanding mechanisms for generation of grid fields.
2011
- </li>A molecular toolbox for rapid generation of viral vectors to up- or down-regulate neuronal gene expression in vivoMelanie D. White , Ruth V. J. Milne , and Matthew F. NolanApr 2011
We introduce a molecular toolbox for manipulation of neuronal gene expression in vivo. The toolbox includes promoters, ion channels, optogenetic tools, fluorescent proteins, and intronic artificial microRNAs. The components are easily assembled into adeno-associated virus (AAV) or lentivirus vectors using recombination cloning. We demonstrate assembly of toolbox components into lentivirus and AAV vectors and use these vectors for in vivo expression of inwardly rectifying potassium channels (Kir2.1, Kir3.1, and Kir3.2) and an artificial microRNA targeted against the ion channel HCN1 (HCN1 miRNA). We show that AAV assembled to express HCN1 miRNA produces efficacious and specific in vivo knockdown of HCN1 channels. Comparison of in vivo viral transduction using HCN1 miRNA with mice containing a germ line deletion of HCN1 reveals similar physiological phenotypes in cerebellar Purkinje cells. The easy assembly and re-usability of the toolbox components, together with the ability to up- or down-regulate neuronal gene expression in vivo, may be useful for applications in many areas of neuroscience.
</li>Tuning of synaptic responses: an organizing principle for optimization of neural circuitsCian O’Donnell , and Matthew F. NolanFeb 2011Neuron types are classically defined by anatomical and physiological properties that determine how synaptic inputs are integrated. Here, we provide an overview of the evidence that, among neurons of a single type, integration of synaptic responses is further tuned according to the particular function that individual neurons carry out. Recent data suggest that tuning of synaptic responses is not restricted to sensory pathways, but extends to cognitive and motor circuits. We propose that tuning of synaptic integration results from general cellular mechanisms for optimization of information processing that are distinct from, but complementary to, homeostasis and memory storage. These cellular tuning mechanisms might be crucial for distributed computations underlying sensory, motor and cognitive functions.
</li>A Critical Role for Neurofascin in Regulating Action Potential Initiation through Maintenance of the Axon Initial SegmentBarbara Zonta , Anne Desmazieres , Arianna Rinaldi , and 4 more authorsMar 2011The axon initial segment (AIS) is critical for the initiation and propagation of action potentials. Assembly of the AIS requires interactions between scaffolding molecules and voltage-gated sodium channels, but the molecular mechanisms that stabilize the AIS are poorly understood. The neuronal isoform of Neurofascin, Nfasc186, clusters voltage-gated sodium channels at nodes of Ranvier in myelinated nerves: here, we investigate its role in AIS assembly and stabilization. Inactivation of the Nfasc gene in cerebellar Purkinje cells of adult mice causes rapid loss of Nfasc186 from the AIS but not from nodes of Ranvier. This causes AIS disintegration, impairment of motor learning and the abolition of the spontaneous tonic discharge typical of Purkinje cells. Nevertheless, action potentials with a modified waveform can still be evoked and basic motor abilities remain intact. We propose that Nfasc186 optimizes communication between mature neurons by anchoring the key elements of the adult AIS complex.
</li>Dorsal-ventral organization of theta-like activity intrinsic to entorhinal stellate neurons is mediated by differences in stochastic current fluctuationsPaul D. Dodson , Hugh Pastoll , and Matthew F. NolanJun 2011The membrane potential dynamics of stellate neurons in layer II of the medial entorhinal cortex are important for neural encoding of location. Previous studies suggest that these neurons generate intrinsic theta-frequency membrane potential oscillations, with a period that depends on neuronal location on the dorsal-ventral axis of the medial entorhinal cortex, and which in behaving animals could support generation of grid-like spatial firing fields. To address the nature and organization of this theta-like activity, we adopt the Lomb method of least-squares spectral analysis. We demonstrate that peaks in frequency spectra that differ significantly from Gaussian noise do not necessarily imply the existence of a periodic oscillator, but can instead arise from filtered stochastic noise or a stochastic random walk. We show that theta-like membrane potential activity recorded from stellate neurons in mature brain slices is consistent with stochastic mechanisms, but not with generation by a periodic oscillator. The dorsal-ventral organization of intrinsic theta-like membrane potential activity, and the modification of this activity during block of HCN channels, both reflect altered frequency distributions of stochastic spectral peaks, rather than tuning of a periodic oscillator. Our results demonstrate the importance of distinguishing periodic oscillations from stochastic processes. We suggest that dorsal-ventral tuning of theta-like membrane potential activity is due to differences in stochastic current fluctuations resulting from organization of ion channels that also control synaptic integration.
</li></ol>Dendritic Spine Dynamics Regulate the Long-Term Stability of Synaptic PlasticityCian O’Donnell , Matthew F. Nolan , and Mark C. W. RossumNov 2011Long-term synaptic plasticity requires postsynaptic influx of Ca(2+) and is accompanied by changes in dendritic spine size. Unless Ca(2+) influx mechanisms and spine volume scale proportionally, changes in spine size will modify spine Ca(2+) concentrations during subsequent synaptic activation. We show that the relationship between Ca(2+) influx and spine volume is a fundamental determinant of synaptic stability. If Ca(2+) influx is undercompensated for increases in spine size, then strong synapses are stabilized and synaptic strength distributions have a single peak. In contrast, overcompensation of Ca(2+) influx leads to binary, persistent synaptic strengths with double-peaked distributions. Biophysical simulations predict that CA1 pyramidal neuron spines are undercompensating. This unifies experimental findings that weak synapses are more plastic than strong synapses, that synaptic strengths are unimodally distributed, and that potentiation saturates for a given stimulus strength. We conclude that structural plasticity provides a simple, local, and general mechanism that allows dendritic spines to foster both rapid memory formation and persistent memory storage.
2010
- </li></ol>Stochastic Ion Channel Gating in Dendritic Neurons: Morphology Dependence and Probabilistic Synaptic Activation of Dendritic SpikesRobert C. Cannon , Cian O’Donnell , and Matthew F. NolanAug 2010
Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites.
2009
- </li></ol>Stochastically Gating Ion Channels Enable Patterned Spike Firing through Activity-Dependent Modulation of Spike ProbabilityJoshua T. Dudman , and Matthew F. NolanFeb 2009
The transformation of synaptic input into patterns of spike output is a fundamental operation that is determined by the particular complement of ion channels that a neuron expresses. Although it is well established that individual ion channel proteins make stochastic transitions between conducting and non-conducting states, most models of synaptic integration are deterministic, and relatively little is known about the functional consequences of interactions between stochastically gating ion channels. Here, we show that a model of stellate neurons from layer II of the medial entorhinal cortex implemented with either stochastic or deterministically gating ion channels can reproduce the resting membrane properties of stellate neurons, but only the stochastic version of the model can fully account for perithreshold membrane potential fluctuations and clustered patterns of spike output that are recorded from stellate neurons during depolarized states. We demonstrate that the stochastic model implements an example of a general mechanism for patterning of neuronal output through activity-dependent changes in the probability of spike firing. Unlike deterministic mechanisms that generate spike patterns through slow changes in the state of model parameters, this general stochastic mechanism does not require retention of information beyond the duration of a single spike and its associated afterhyperpolarization. Instead, clustered patterns of spikes emerge in the stochastic model of stellate neurons as a result of a transient increase in firing probability driven by activation of HCN channels during recovery from the spike afterhyperpolarization. Using this model, we infer conditions in which stochastic ion channel gating may influence
2008
- </li></ol>Tuning of Synaptic Integration in the Medial Entorhinal Cortex to the Organization of Grid Cell Firing FieldsDerek L. F. Garden , Paul D. Dodson , Cian O’Donnell , and 2 more authorsDec 2008
Neurons important for cognitive function are often classified by their morphology and integrative properties. However, it is unclear if within a single class of neuron these properties tune synaptic responses to the salient features of the information that each neuron represents. We demonstrate that for stellate neurons in layer 11 of the medial entorhinal cortex, the waveform of postsynaptic potentials, the time window for detection of coincident inputs, and responsiveness to gamma frequency inputs follow a dorsal-ventral gradient similar to the topographical organization of grid-like spatial firing fields of neurons in this area. We provide evidence that these differences are due to a membrane conductance gradient mediated by HCN and leak potassium channels. These findings suggest key roles for synaptic integration in computations carried out within the medial entorhinal cortex and imply that tuning of neural information processing by membrane ion channels is important for normal cognitive function.
2007
- </li></ol>HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortexMatthew F. Nolan , Joshua T. Dudman , Paul D. Dodson , and 1 more authorNov 2007
Whereas recent studies have elucidated principles for representation of information within the entorhinal cortex, less is known about the molecular basis for information processing by entorhinal neurons. The HCN1 gene encodes ion channels that mediate hyperpolarization-activated currents (I-h) that control synaptic integration and influence several forms of learning and memory. We asked whether hyperpolarization-activated, cation nonselective 1 (HCN1) channels control processing of information by stellate cells found within layer II of the entorhinal cortex. Axonal projections from these neurons form a major component of the synaptic input to the dentate gyrus of the hippocampus. To determine whether HCN1 channels control either the resting or the active properties of stellate neurons, we performed whole-cell recordings in horizontal brain slices prepared from adult wild-type and HCN1 knock-out mice. We found that HCN1 channels are required for rapid and full activation of hyperpolarization-activated currents in stellate neurons. HCN1 channels dominate the membrane conductance at rest, are not required for theta frequency (4-12 Hz) membrane potential fluctuations, but suppress low-frequency (< 4 Hz) components of spontaneous and evoked membrane potential activity. During sustained activation of stellate cells sufficient for firing of repeated action potentials, HCN1 channels control the pattern of spike output by promoting recovery of the spike afterhyperpolarization. These data suggest that HCN1 channels expressed by stellate neurons in layer II of the entorhinal cortex are key molecular components in the processing of inputs to the hippocampal dentate gyrus, with distinct integrative roles during resting and active states.
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