RESUMO
Sensory processing in the neocortex requires both feedforward and feedback information flow between cortical areas1. In feedback processing, higher-level representations provide contextual information to lower levels, and facilitate perceptual functions such as contour integration and figure-ground segmentation2,3. However, we have limited understanding of the circuit and cellular mechanisms that mediate feedback influence. Here we use long-range all-optical connectivity mapping in mice to show that feedback influence from the lateromedial higher visual area (LM) to the primary visual cortex (V1) is spatially organized. When the source and target of feedback represent the same area of visual space, feedback is relatively suppressive. By contrast, when the source is offset from the target in visual space, feedback is relatively facilitating. Two-photon calcium imaging data show that this facilitating feedback is nonlinearly integrated in the apical tuft dendrites of V1 pyramidal neurons: retinotopically offset (surround) visual stimuli drive local dendritic calcium signals indicative of regenerative events, and two-photon optogenetic activation of LM neurons projecting to identified feedback-recipient spines in V1 can drive similar branch-specific local calcium signals. Our results show how neocortical feedback connectivity and nonlinear dendritic integration can together form a substrate to support both predictive and cooperative contextual interactions.
Assuntos
Dendritos , Retroalimentação Fisiológica , Córtex Visual , Vias Visuais , Animais , Camundongos , Cálcio/metabolismo , Dendritos/fisiologia , Córtex Visual/citologia , Córtex Visual/fisiologia , Vias Visuais/citologia , Vias Visuais/fisiologia , Retroalimentação Fisiológica/fisiologia , Córtex Visual Primário/citologia , Córtex Visual Primário/fisiologia , Células Piramidais/citologia , Células Piramidais/fisiologia , Optogenética , Sinalização do CálcioRESUMO
Task-optimized convolutional neural networks (CNNs) show striking similarities to the ventral visual stream. However, human-imperceptible image perturbations can cause a CNN to make incorrect predictions. Here we provide insight into this brittleness by investigating the representations of models that are either robust or not robust to image perturbations. Theory suggests that the robustness of a system to these perturbations could be related to the power law exponent of the eigenspectrum of its set of neural responses, where power law exponents closer to and larger than one would indicate a system that is less susceptible to input perturbations. We show that neural responses in mouse and macaque primary visual cortex (V1) obey the predictions of this theory, where their eigenspectra have power law exponents of at least one. We also find that the eigenspectra of model representations decay slowly relative to those observed in neurophysiology and that robust models have eigenspectra that decay slightly faster and have higher power law exponents than those of non-robust models. The slow decay of the eigenspectra suggests that substantial variance in the model responses is related to the encoding of fine stimulus features. We therefore investigated the spatial frequency tuning of artificial neurons and found that a large proportion of them preferred high spatial frequencies and that robust models had preferred spatial frequency distributions more aligned with the measured spatial frequency distribution of macaque V1 cells. Furthermore, robust models were quantitatively better models of V1 than non-robust models. Our results are consistent with other findings that there is a misalignment between human and machine perception. They also suggest that it may be useful to penalize slow-decaying eigenspectra or to bias models to extract features of lower spatial frequencies during task-optimization in order to improve robustness and V1 neural response predictivity.
Assuntos
Modelos Neurológicos , Redes Neurais de Computação , Córtex Visual Primário , Algoritmos , Animais , Biologia Computacional , Humanos , Macaca fascicularis , Camundongos , Neurônios/citologia , Neurônios/fisiologia , Córtex Visual Primário/citologia , Córtex Visual Primário/fisiologiaRESUMO
Motion/direction-sensitive and location-sensitive neurons are the two major functional types in mouse visual thalamus that project to the primary visual cortex (V1). It is under debate whether motion/direction-sensitive inputs preferentially target the superficial layers in V1, as opposed to the location-sensitive inputs, which preferentially target the middle layers. Here, by using calcium imaging to measure the activity of motion/direction-sensitive and location-sensitive axons in V1, we find evidence against these cell-type-specific laminar biases at the population level. Furthermore, using an approach to reconstruct axon arbors with identified in vivo response types, we show that, at the single-axon level, the motion/direction-sensitive axons project more densely to the middle layers than the location-sensitive axons. Overall, our results demonstrate that motion/direction-sensitive thalamic neurons project extensively to the middle layers of V1 at both the population and single-cell levels, providing further insight into the organization of thalamocortical projection in the mouse visual system.
Assuntos
Axônios/fisiologia , Percepção de Movimento , Orientação , Córtex Visual Primário/fisiologia , Tálamo/fisiologia , Animais , Sinalização do Cálcio , Feminino , Masculino , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência por Excitação Multifotônica , Estimulação Luminosa , Córtex Visual Primário/citologia , Tálamo/citologia , Vias Visuais/citologia , Vias Visuais/fisiologiaRESUMO
The brain adapts to the sensory environment. For example, simple sensory exposure can modify the response properties of early sensory neurons. How these changes affect the overall encoding and maintenance of stimulus information across neuronal populations remains unclear. We perform parallel recordings in the primary visual cortex of anesthetized cats and find that brief, repetitive exposure to structured visual stimuli enhances stimulus encoding by decreasing the selectivity and increasing the range of the neuronal responses that persist after stimulus presentation. Low-dimensional projection methods and simple classifiers demonstrate that visual exposure increases the segregation of persistent neuronal population responses into stimulus-specific clusters. These observed refinements preserve the representational details required for stimulus reconstruction and are detectable in postexposure spontaneous activity. Assuming response facilitation and recurrent network interactions as the core mechanisms underlying stimulus persistence, we show that the exposure-driven segregation of stimulus responses can arise through strictly local plasticity mechanisms, also in the absence of firing rate changes. Our findings provide evidence for the existence of an automatic, unguided optimization process that enhances the encoding power of neuronal populations in early visual cortex, thus potentially benefiting simple readouts at higher stages of visual processing.
Assuntos
Córtex Visual Primário/fisiologia , Adaptação Fisiológica , Animais , Gatos , Potenciais Evocados Visuais/fisiologia , Feminino , Masculino , Modelos Neurológicos , Rede Nervosa/fisiologia , Plasticidade Neuronal , Estimulação Luminosa/métodos , Córtex Visual Primário/citologia , Recrutamento Neurofisiológico , Células Receptoras Sensoriais/fisiologia , Percepção Visual/fisiologiaRESUMO
This paper offers a theory for the origin of direction selectivity (DS) in the macaque primary visual cortex, V1. DS is essential for the perception of motion and control of pursuit eye movements. In the macaque visual pathway, neurons with DS first appear in V1, in the Simple cell population of the Magnocellular input layer 4Cα. The lateral geniculate nucleus (LGN) cells that project to these cortical neurons, however, are not direction selective. We hypothesize that DS is initiated in feed-forward LGN input, in the summed responses of LGN cells afferent to a cortical cell, and it is achieved through the interplay of 1) different visual response dynamics of ON and OFF LGN cells and 2) the wiring of ON and OFF LGN neurons to cortex. We identify specific temporal differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated subregions; analysis and simulations confirm the efficacy of the mechanisms proposed. To constrain the theory, we present data on Simple cells in layer 4Cα in response to drifting gratings. About half of the cells were found to have high DS, and the DS was broadband in spatial and temporal frequency (SF and TF). The proposed theory includes a complete analysis of how stimulus features such as SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to determine the preferred direction and magnitude of DS.
Assuntos
Corpos Geniculados/citologia , Córtex Visual Primário/fisiologia , Percepção Visual/fisiologia , Animais , Corpos Geniculados/fisiologia , Macaca fascicularis , Masculino , Modelos Biológicos , Neurônios/fisiologia , Córtex Visual Primário/citologia , Tempo de ReaçãoRESUMO
Through the corpus callosum, interhemispheric communication is mediated by callosal projection (CP) neurons. Using retrograde labeling, we identified a population of layer 6 (L6) excitatory neurons as the main conveyer of transcallosal information in the monocular zone of the mouse primary visual cortex (V1). Distinct from L6 corticothalamic (CT) population, V1 L6 CP neurons contribute to an extensive reciprocal network across multiple sensory cortices over two hemispheres. Receiving both local and long-range cortical inputs, they encode orientation, direction, and receptive field information, while are also highly spontaneous active. The spontaneous activity of L6 CP neurons exhibits complex relationships with brain states and stimulus presentation, distinct from the spontaneous activity patterns of the CT population. The anatomical and functional properties of these L6 CP neurons enable them to broadcast visual and nonvisual information across two hemispheres, and thus may play a role in regulating and coordinating brain-wide activity events.
Assuntos
Corpo Caloso/fisiologia , Neurônios/fisiologia , Estimulação Luminosa/métodos , Córtex Visual Primário/fisiologia , Vias Visuais/fisiologia , Animais , Corpo Caloso/química , Corpo Caloso/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Neurônios/química , Córtex Visual Primário/química , Córtex Visual Primário/citologia , Vias Visuais/química , Vias Visuais/citologiaRESUMO
It is widely assumed that trial-by-trial variability in visual detection performance is explained by the fidelity of visual responses in visual cortical areas influenced by fluctuations of internal states, such as vigilance and behavioral history. However, it is not clear which neuronal ensembles represent such different internal states. Here, we utilized a visual detection task, which distinguishes internal states in response to identical stimuli, while recording neurons simultaneously from the primary visual cortex (V1) and the posterior parietal cortex (PPC). We found that rats sometimes withheld their responses to visual stimuli despite the robust presence of visual responses in V1. Our unsupervised analysis revealed distinct population dynamics segregating hit responses from misses, orthogonally embedded to visual response dynamics in both V1 and PPC. Heterogeneous non-sensory neurons in V1 and PPC significantly contributed to population-level encoding accompanied with the modulation of noise correlation only in V1. These results highlight the non-trivial contributions of non-sensory neurons in V1 and PPC for population-level computations that reflect the animals' internal states to drive behavioral responses to visual stimuli.
Assuntos
Tomada de Decisões , Neurônios/fisiologia , Córtex Visual Primário/citologia , Córtex Visual Primário/fisiologia , Percepção Visual/fisiologia , Animais , Masculino , Lobo Parietal/fisiologia , Estimulação Luminosa , Ratos , Ratos Long-EvansRESUMO
Individual neurons in visual cortex provide the brain with unreliable estimates of visual features. It is not known whether the single-neuron variability is correlated across large neural populations, thus impairing the global encoding of stimuli. We recorded simultaneously from up to 50,000 neurons in mouse primary visual cortex (V1) and in higher order visual areas and measured stimulus discrimination thresholds of 0.35° and 0.37°, respectively, in an orientation decoding task. These neural thresholds were almost 100 times smaller than the behavioral discrimination thresholds reported in mice. This discrepancy could not be explained by stimulus properties or arousal states. Furthermore, behavioral variability during a sensory discrimination task could not be explained by neural variability in V1. Instead, behavior-related neural activity arose dynamically across a network of non-sensory brain areas. These results imply that perceptual discrimination in mice is limited by downstream decoders, not by neural noise in sensory representations.
Assuntos
Discriminação Psicológica/fisiologia , Neurônios/fisiologia , Córtex Visual Primário/fisiologia , Percepção Visual , Animais , Nível de Alerta , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa , Estimulação Luminosa , Córtex Visual Primário/citologia , Limiar SensorialRESUMO
Fluorescent calcium indicators are often used to investigate neural dynamics, but the relationship between fluorescence and action potentials (APs) remains unclear. Most APs can be detected when the soma almost fills the microscope's field of view, but calcium indicators are used to image populations of neurons, necessitating a large field of view, generating fewer photons per neuron, and compromising AP detection. Here, we characterized the AP-fluorescence transfer function in vivo for 48 layer 2/3 pyramidal neurons in primary visual cortex, with simultaneous calcium imaging and cell-attached recordings from transgenic mice expressing GCaMP6s or GCaMP6f. While most APs were detected under optimal conditions, under conditions typical of population imaging studies, only a minority of 1 AP and 2 AP events were detected (often <10% and ~20-30%, respectively), emphasizing the limits of AP detection under more realistic imaging conditions.
Neurons, the cells that make up the nervous system, transmit information using electrical signals known as action potentials or spikes. Studying the spiking patterns of neurons in the brain is essential to understand perception, memory, thought, and behaviour. One way to do that is by recording electrical activity with microelectrodes. Another way to study neuronal activity is by using molecules that change how they interact with light when calcium binds to them, since changes in calcium concentration can be indicative of neuronal spiking. That change can be observed with specialized microscopes know as two-photon fluorescence microscopes. Using calcium indicators, it is possible to simultaneously record hundreds or even thousands of neurons. However, calcium fluorescence and spikes do not translate one-to-one. In order to interpret fluorescence data, it is important to understand the relationship between the fluorescence signals and the spikes associated with individual neurons. The only way to directly measure this relationship is by using calcium imaging and electrical recording simultaneously to record activity from the same neuron. However, this is extremely challenging experimentally, so this type of data is rare. To shed some light on this, Huang, Ledochowitsch et al. used mice that had been genetically modified to produce a calcium indicator in neurons of the visual cortex and simultaneously obtained both fluorescence measurements and electrical recordings from these neurons. These experiments revealed that, while the majority of time periods containing multi-spike neural activity could be identified using calcium imaging microscopy, on average, less than 10% of isolated single spikes were detectable. This is an important caveat that researchers need to take into consideration when interpreting calcium imaging results. These findings are intended to serve as a guide for interpreting calcium imaging studies that look at neurons in the mammalian brain at the population level. In addition, the data provided will be useful as a reference for the development of activity sensors, and to benchmark and improve computational approaches for detecting and predicting spikes.
Assuntos
Potenciais de Ação/fisiologia , Proteínas de Ligação ao Cálcio , Cálcio , Corantes Fluorescentes , Animais , Cálcio/análise , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Corantes Fluorescentes/análise , Corantes Fluorescentes/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Córtex Visual Primário/citologia , Córtex Visual Primário/fisiologia , Células Piramidais/citologia , Células Piramidais/metabolismoRESUMO
During development, the visual system maintains a high capacity for modification by expressing characteristics permissive for plasticity, enabling neural circuits to be refined by visual experience to achieve their mature form. This period is followed by the emergence of characteristics that stabilize the brain to consolidate for lifetime connections that were informed by experience. Attenuation of plasticity potential is thought to derive from an accumulation of plasticity-inhibiting characteristics that appear at ages beyond the peak of plasticity. Perineuronal nets (PNNs) are molecular aggregations that primarily surround fast-spiking inhibitory neurons called parvalbumin (PV) cells, which exhibit properties congruent with a plasticity inhibitor. In this study, we examined the development of PNNs and PV cells in the primary visual cortex of a highly visual mammal, and assessed the impact that 10 days of darkness had on both characteristics. Here, we show that labeling for PV expression emerges earlier and reaches adult levels sooner than PNNs. We also demonstrate that darkness, a condition known to enhance plasticity, significantly reduces the density of PNNs and the size of PV cell somata but does not alter the number of PV cells in the visual cortex. The darkness-induced reduction of PV cell size occurred irrespective of whether neurons were surrounded by a PNN, suggesting that PNNs have a restricted capacity to inhibit plasticity. Finally, we show that PV cells surrounded by a PNN were significantly larger than those without one, supporting the view that PNNs may mediate trophic support to the cells they surround.
Assuntos
Escuridão , Rede Nervosa/crescimento & desenvolvimento , Neurônios/fisiologia , Parvalbuminas/fisiologia , Córtex Visual Primário/crescimento & desenvolvimento , Fatores Etários , Animais , Gatos , Rede Nervosa/química , Neurônios/química , Parvalbuminas/análise , Córtex Visual Primário/química , Córtex Visual Primário/citologiaRESUMO
Activation of the heart normally begins in the sinoatrial node (SAN). Electrical impulses spontaneously released by SAN pacemaker cells (SANPCs) trigger the contraction of the heart. However, the cellular nature of SANPCs remains controversial. Here, we report that SANPCs exhibit glutamatergic neuron-like properties. By comparing the single-cell transcriptome of SANPCs with that of cells from primary visual cortex in mouse, we found that SANPCs co-clustered with cortical neurons. Tissue and cellular imaging confirmed that SANPCs contained key elements of glutamatergic neurotransmitter system, expressing genes encoding glutamate synthesis pathway (Gls), ionotropic and metabotropic glutamate receptors (Grina, Gria3, Grm1 and Grm5), and glutamate transporters (Slc17a7). SANPCs highly expressed cell markers of glutamatergic neurons (Snap25 and Slc17a7), whereas Gad1, a marker of GABAergic neurons, was negative. Functional studies revealed that inhibition of glutamate receptors or transporters reduced spontaneous pacing frequency of isolated SAN tissues and spontaneous Ca2+ transients frequency in single SANPC. Collectively, our work suggests that SANPCs share dominant biological properties with glutamatergic neurons, and the glutamatergic neurotransmitter system may act as an intrinsic regulation module of heart rhythm, which provides a potential intervention target for pacemaker cell-associated arrhythmias.
Assuntos
Relógios Biológicos/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Córtex Visual Primário/metabolismo , Nó Sinoatrial/metabolismo , Transcriptoma , Potenciais de Ação/fisiologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Cálcio/metabolismo , Proteínas de Transporte/classificação , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Córtex Visual Primário/citologia , Receptores Ionotrópicos de Glutamato/classificação , Receptores Ionotrópicos de Glutamato/genética , Receptores Ionotrópicos de Glutamato/metabolismo , Receptores de Glutamato Metabotrópico/classificação , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Análise de Célula Única , Nó Sinoatrial/citologia , Técnicas de Cultura de Tecidos , Ácido gama-Aminobutírico/metabolismoRESUMO
Locomotion creates various patterns of optic flow on the retina, which provide the observer with information about their movement relative to the environment. However, it is unclear how these optic flow patterns are encoded by the cortex. Here, we use two-photon calcium imaging in awake mice to systematically map monocular and binocular responses to horizontal motion in four areas of the visual cortex. We find that neurons selective to translational or rotational optic flow are abundant in higher visual areas, whereas neurons suppressed by binocular motion are more common in the primary visual cortex. Disruption of retinal direction selectivity in Frmd7 mutant mice reduces the number of translation-selective neurons in the primary visual cortex and translation- and rotation-selective neurons as well as binocular direction-selective neurons in the rostrolateral and anterior visual cortex, blurring the functional distinction between primary and higher visual areas. Thus, optic flow representations in specific areas of the visual cortex rely on binocular integration of motion information from the retina.
Assuntos
Fluxo Óptico , Córtex Visual Primário/fisiologia , Retina/metabolismo , Visão Binocular , Animais , Feminino , Masculino , Camundongos , Neurônios/fisiologia , Córtex Visual Primário/citologia , Vias VisuaisRESUMO
The extrageniculate visual pathway, which carries visual information from the retina through the superficial layers of the superior colliculus and the pulvinar, is poorly understood. The pulvinar is thought to modulate information flow between cortical areas, and has been implicated in cognitive tasks like directing visually guided actions. In order to better understand the underlying circuitry, we performed retrograde injections of modified rabies virus in the visual cortex and pulvinar of the Long-Evans rat. We found a relatively small population of cells projecting to primary visual cortex (V1), compared to a much larger population projecting to higher visual cortex. Reciprocal corticothalamic projections showed a similar result, implying that pulvinar does not play as big a role in directly modulating rodent V1 activity as previously thought.
Assuntos
Córtex Visual Primário/anatomia & histologia , Pulvinar/anatomia & histologia , Vias Visuais/anatomia & histologia , Animais , Feminino , Córtex Visual Primário/citologia , Pulvinar/citologia , Ratos , Ratos Long-Evans , Córtex Visual/anatomia & histologia , Córtex Visual/citologia , Vias Visuais/citologiaRESUMO
Orientation preference maps (OPMs) are a prominent feature of primary visual cortex (V1) organization in many primates and carnivores. In rodents, neurons are not organized in OPMs but are instead interspersed in a "salt and pepper" fashion, although clusters of orientation-selective neurons have been reported. Does this fundamental difference reflect the existence of a lower size limit for orientation columns (OCs) below which they cannot be scaled down with decreasing V1 size? To address this question, we examined V1 of one of the smallest living primates, the 60-g prosimian mouse lemur (Microcebus murinus). Using chronic intrinsic signal imaging, we found that mouse lemur V1 contains robust OCs, which are arranged in a pinwheel-like fashion. OC size in mouse lemurs was found to be only marginally smaller compared to the macaque, suggesting that these circuit elements are nearly incompressible. The spatial arrangement of pinwheels is well described by a common mathematical design of primate V1 circuit organization. In order to accommodate OPMs, we found that the mouse lemur V1 covers one-fifth of the cortical surface, which is one of the largest V1-to-cortex ratios found in primates. These results indicate that the primate-type visual cortical circuit organization is constrained by a size limitation and raises the possibility that its emergence might have evolved by disruptive innovation rather than gradual change.
Assuntos
Cheirogaleidae , Córtex Visual Primário/anatomia & histologia , Córtex Visual Primário/fisiologia , Animais , Cheirogaleidae/anatomia & histologia , Cheirogaleidae/fisiologia , Feminino , Masculino , Modelos Neurológicos , Neurônios/fisiologia , Orientação , Córtex Visual Primário/citologiaRESUMO
Synapses are involved in the communication of information from one neuron to another. However, a systematic analysis of synapse density in the neocortex from a diversity of species is lacking, limiting what can be understood about the evolution of this fundamental aspect of brain structure. To address this, we quantified synapse density in supragranular layers II-III and infragranular layers V-VI from primary visual cortex and inferior temporal cortex in a sample of 25 species of primates, including humans. We found that synapse densities were relatively constant across these levels of the cortical visual processing hierarchy and did not significantly differ with brain mass, varying by only 1.9-fold across species. We also found that neuron densities decreased in relation to brain enlargement. Consequently, these data show that the number of synapses per neuron significantly rises as a function of brain expansion in these neocortical areas of primates. Humans displayed the highest number of synapses per neuron, but these values were generally within expectations based on brain size. The metabolic and biophysical constraints that regulate uniformity of synapse density, therefore, likely underlie a key principle of neuronal connectivity scaling in primate neocortical evolution.
Assuntos
Evolução Biológica , Neocórtex/citologia , Neurônios/citologia , Primatas/anatomia & histologia , Sinapses , Adulto , Animais , Feminino , Humanos , Masculino , Córtex Visual Primário/citologia , Lobo Temporal/citologia , Adulto JovemRESUMO
The cerebral cortex of primates encompasses multiple anatomically and physiologically distinct areas processing visual information. Areas V1, V2, and V5/MT are conserved across mammals and are central for visual behavior. To facilitate the generation of biologically accurate computational models of primate early visual processing, here we provide an overview of over 350 published studies of these three areas in the genus Macaca, whose visual system provides the closest model for human vision. The literature reports 14 anatomical connection types from the lateral geniculate nucleus of the thalamus to V1 having distinct layers of origin or termination, and 194 connection types between V1, V2, and V5, forming multiple parallel and interacting visual processing streams. Moreover, within V1, there are reports of 286 and 120 types of intrinsic excitatory and inhibitory connections, respectively. Physiologically, tuning of neuronal responses to 11 types of visual stimulus parameters has been consistently reported. Overall, the optimal spatial frequency (SF) of constituent neurons decreases with cortical hierarchy. Moreover, V5 neurons are distinct from neurons in other areas for their higher direction selectivity, higher contrast sensitivity, higher temporal frequency tuning, and wider SF bandwidth. We also discuss currently unavailable data that could be useful for biologically accurate models.