Thalamocortical synapses in the cat visual system in vivo are weak and unreliable.

The thalamocortical synapse of the visual system has been central to our understanding of sensory computations in the cortex. Although we have a fair understanding of the functional properties of the pre and post-synaptic populations, little is known about their synaptic properties, particularly in vivo. We used simultaneous recordings in LGN and V1 in cat in vivo to characterize the dynamic properties of thalamocortical synaptic transmission in monosynaptically connected LGN-V1 neurons. We found that thalamocortical synapses in vivo are unreliable, highly variable and exhibit short-term plasticity. Using biologically constrained models, we found that variable and unreliable synapses serve to increase cortical firing by means of increasing membrane fluctuations, similar to high conductance states. Thus, synaptic variability and unreliability, rather than acting as system noise, do serve a computational function. Our characterization of LGN-V1 synaptic properties constrains existing mathematical models, and mechanistic hypotheses, of a fundamental circuit in computational neuroscience.

Inhibition in Simple Cell Receptive Fields Is Broad and OFF-Subregion Biased.

Inhibition in thalamorecipient layer 4 simple cells of primary visual cortex is believed to play important roles in establishing visual response properties and integrating visual inputs across their receptive fields (RFs). Simple cell RFs are characterized by nonoverlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the firing rate of the cell, depending on contrast. Inhibition is believed to be triggered exclusively from visual stimulation of individual RF subregions. However, this view is at odds with the known anatomy of layer 4 interneurons in visual cortex and differs from recent findings in mouse visual cortex. Here we show with in vivo intracellular recordings in cats that while excitation is restricted to RF subregions, inhibition spans the width of simple cell RFs. Consequently, excitatory stimuli within a subregion concomitantly drive excitation and inhibition. Furthermore, we found that the distribution of inhibition across the RF is stronger toward OFF subregions. This inhibitory OFF-subregion bias has a functional consequence on spatial integration of inputs across the RF. A model based on the known anatomy of layer 4 demonstrates that the known proportion and connectivity of inhibitory neurons in layer 4 of primary visual cortex is sufficient to explain broad inhibition with an OFF-subregion bias while generating a variety of phase relations, including antiphase, between excitation and inhibition in response to drifting gratings.SIGNIFICANCE STATEMENT The wiring of excitatory and inhibitory neurons in cortical circuits is key to determining the response properties in sensory cortex. In the visual cortex, the first cells that receive visual input are simple cells in layer 4. The underlying circuitry responsible for the response properties of simple cells is not yet known. In this study, we challenge a long-held view concerning the pattern of inhibitory input and provide results that agree with current known anatomy. We show here that inhibition is evoked broadly across the receptive fields of simple cells, and we identify a surprising bias in inhibition within the receptive field. Our findings represent a step toward a unified view of inhibition across different species and sensory systems.

Intracellular, In Vivo, Dynamics of Thalamocortical Synapses in Visual Cortex.

Seminal studies of the thalamocortical circuit in the visual system of the cat have been central to our understanding of sensory encoding. However, thalamocortical synaptic properties remain poorly understood. We used paired recordings, in the lateral geniculate nucleus (LGN) and primary visual cortex (V1), to provide the first in vivo characterization of sensory-driven thalamocortical potentials in V1. The amplitudes of EPSPs we characterized were smaller than those previously reported in vitro Consistent with prior findings, connected LGN-V1 pairs were only found when their receptive fields (RFs) overlapped, and the probability of connection increased steeply with degree of RF overlap and response similarity. However, surprisingly, we found no relationship between EPSP amplitudes and the similarity of RFs or responses, suggesting different connectivity models for intracortical and thalamocortical circuits. Putative excitatory regular-spiking (RS) and inhibitory fast-spiking (FS) V1 cells had similar EPSP characteristics, showing that in the visual system, feedforward excitation and inhibition are driven with equal strength by the thalamus. Similar to observations in the somatosensory cortex, FS V1 cells received less specific input from LGN. Finally, orientation tuning in V1 was not inherited from single presynaptic LGN cells, suggesting that it must emerge exclusively from the combined input of all presynaptic LGN cells. Our results help to decipher early visual encoding circuits and have immediate utility in providing physiological constraints to computational models of the visual system.SIGNIFICANCE STATEMENT To understand how the brain encodes the visual environment, we must understand the transfer of visual signals between various regions of the brain. Therefore, understanding synaptic dynamics is critical to our understanding of sensory encoding. This study provides the first characterization of visually evoked synaptic potentials between the visual thalamus and visual cortex in an intact animal. To record these potentials, we simultaneously recorded the extracellular potential of presynaptic thalamic cells and the intracellular potential of postsynaptic cortical cells in input layers of primary visual cortex. Our characterization of synaptic potentials in vivo disagreed with prior findings in vitro This study will increase our understanding of thalamocortical circuits and will improve computational models of visual encoding.

Synaptic mechanisms of temporal diversity in the lateral geniculate nucleus of the thalamus.

The lateral geniculate nucleus (LGN) contains a unique and numerous class of cells called lagged cells, which introduce a time delay into the neural signal provided to cortex. Previous studies have shown that this delay is dependent on GABA(A) receptors within the LGN. Furthermore, lagged cells have distinct integrative properties with a slower rising, more sustained, and overall lower firing rates than nonlagged cells. We have recorded intracellularly from lagged cells in the cat LGN and found a unique property of their retinal inputs that underlies both their temporal and integrative visual response properties. Lagged cell EPSPs, which often derive from a single retinal input, have smaller amplitudes, repolarize more quickly, and are followed by a Cl(-)-dependent hyperpolarization compared with nonlagged cells. The Cl(-)-dependent hyperpolarization sums early in the visual response generating a powerful synaptic inhibition that coincides with the peak frequency of retinal input and delays the spike response in lagged cells. The hyperpolarization subsides rapidly over ∼20-40 ms allowing for slow summation of the retinal input leading to the visual spike response. Given the tight association of single retinal EPSPs and the following inhibition, we propose that both functional properties result from the triadic circuitry prevalent in the LGN and particularly prominent in lagged X-cells. Thus, our results show for the first time a dynamic interaction of retinal excitation and fast feedforward inhibition that determines the integrative properties and the delay in firing of lagged cells.

Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo.

Arrays of electrodes for recording and stimulating the brain are used throughout clinical medicine and basic neuroscience research, yet are unable to sample large areas of the brain while maintaining high spatial resolution because of the need to individually wire each passive sensor at the electrode-tissue interface. To overcome this constraint, we developed new devices that integrate ultrathin and flexible silicon nanomembrane transistors into the electrode array, enabling new dense arrays of thousands of amplified and multiplexed sensors that are connected using fewer wires. We used this system to record spatial properties of cat brain activity in vivo, including sleep spindles, single-trial visual evoked responses and electrographic seizures. We found that seizures may manifest as recurrent spiral waves that propagate in the neocortex. The developments reported here herald a new generation of diagnostic and therapeutic brain-machine interface devices.

Cellular mechanisms of temporal sensitivity in visual cortex neurons.

The ability of cortical neurons to accurately encode the temporal pattern of their inputs has important consequences for cortical function and perceptual acuity. Here we identify cellular mechanisms underlying the sensitivity of cortical neurons to the timing of sensory-evoked synaptic inputs. We find that temporally coincident inputs to layer 4 neurons in primary visual cortex evoke an increase in spike precision and supralinear spike summation. Underlying this nonlinear summation are changes in the evoked excitatory conductance and the associated membrane potential response, and a lengthening of the window between excitation and inhibition. Furthermore, fast-spiking inhibitory interneurons in layer 4 exhibit a shorter window of temporal sensitivity compared with excitatory neurons. In contrast to the enhanced response to synchronous inputs by layer 4 neurons, sensory input integration in downstream cortical layers is more linear and less sensitive to timing. Neurons in the input layer of cortex are thus uniquely optimized to detect and encode synchronous sensory-evoked inputs.

Cellular mechanisms underlying stimulus-dependent gain modulation in primary visual cortex neurons in vivo.

Gain modulation is a widespread neuronal phenomenon that modifies response amplitude without changing selectivity. Computational and in vitro studies have proposed cellular mechanisms of gain modulation based on the postsynaptic effects of background synaptic activation, but these mechanisms have not been studied in vivo. Here, we used intracellular recordings from cat primary visual cortex to measure neuronal gain while changing background synaptic activity with visual stimulation. We found that increases in the membrane fluctuations associated with increases in synaptic input do not obligatorily result in gain modulation in vivo. However, visual stimuli that evoked sustained changes in resting membrane potential, input resistance, and membrane fluctuations robustly modulated neuronal gain. The magnitude of gain modulation depended critically on the spatiotemporal properties of the visual stimulus. Gain modulation in vivo may thus be determined on a moment-to-moment basis by sensory context and the consequent dynamics of synaptic activation.

Stimulus feature selectivity in excitatory and inhibitory neurons in primary visual cortex.

Although several lines of evidence suggest that stimulus selectivity in somatosensory and visual cortices is critically dependent on unselective inhibition, particularly in the thalamorecipient layer 4, no comprehensive comparison of the responses of excitatory and inhibitory cells has been conducted. Here, we recorded intracellularly from a large population of regular spiking (RS; presumed excitatory) and fast spiking (FS; presumed inhibitory) cells in layers 2-6 of primary visual cortex. In layer 4, where selectivity for orientation and spatial frequency first emerges, we found no untuned FS cells. Instead, the tuning of the spike output of layer 4 FS cells was significantly but moderately broader than that of RS cells. However, the tuning of the underlying synaptic responses was not different, indicating that the difference in spike-output selectivity resulted from differences in the transformation of synaptic input into firing rate. Layer 4 FS cells exhibited significantly lower input resistance and faster time constants than layer 4 RS cells, leading to larger and faster membrane potential (V(m)) fluctuations. FS cell V(m) fluctuations were more broadly tuned than those of RS cells and matched spike-output tuning, suggesting that the broader spike tuning of these cells was driven by visually evoked synaptic noise. These differences were not observed outside of layer 4. Thus, cell type-specific differences in stimulus feature selectivity at the first level of cortical sensory processing may arise as a result of distinct biophysical properties that determine the dynamics of synaptic integration.

Viewpoint: developing a research ethics consultation service to foster responsive and responsible clinical research.

Although clinical ethics has become a central, and welcome, component of the health care landscape, research ethics consultation services are still uncommon. Indeed, the usual approach to ethical concerns in research with human subjects has been primarily a regulatory one. Nonetheless, ethical problems also arise in the context of research and thus collaborations between investigators and research ethicists are as essential as those between physicians and clinical ethicists. The authors argue that the use of research ethics consultation services can be of benefit to clinical scientists, bioethicists, research institutions, and research subjects. Such services can increase sensitivity among researchers to the ethical implications of their work, result in better institutional research policies, and facilitate the development of an organizational culture that is receptive to the identification and resolution of ethical conflicts. The authors conclude by describing the process of development and implementation of such a research ethics consultation service at Weill Medical College of Cornell University.

Precision, reliability, and information-theoretic analysis of visual thalamocortical neurons.

High-order statistics of neural responses allow one to gain insight into neural function that may not be evident from firing rate alone. In this study, we compared the precision, reliability, and information content of spike trains from X- and Y-cells in the lateral geniculate nucleus (LGN) and layer IV simple cells of area 17 in the cat. To a stochastic, contrast-modulated Gabor patch, layer IV simple cells responded as precisely as their primary inputs, LGN X-cells, but less reliably. LGN Y-cells were more precise and reliable than LGN X-cells. Also, within each LGN cell type, 1) responses to the same stimulus were nearly identical if they shared the same center sign and 2) responses of neurons with the same center sign were nearly identical to the responses of neurons of opposite center sign if the stimulus' contrasts were inverted. These results suggest simple cells receive highly precise and synchronous LGN input, resulting in precise responses. Nonetheless, the response precision of simple cells was greater than expected. Finally, information-theoretic calculations of our cell responses revealed that 1) LGN X-cells encoded information at half the rate of LGN Y-cells but 2.5 times the rate of layer IV simple cells; 2) LGN cells encoded information in their responses using temporal patterns, whereas simple cells did not; and 3) simple cells used more of their information capacity than LGN X-cells. We propose mechanisms that simple cells might use to ensure high precision.

Stimulus-dependent gamma (30-50 Hz) oscillations in simple and complex fast rhythmic bursting cells in primary visual cortex.

Oscillatory activity is generated by many neural systems. gamma band (approximately 40 Hz) oscillations in the thalamus and cortex occur spontaneously and in response to sensory stimuli. Fast rhythmic bursting (FRB) cells (also called chattering cells) comprise a unique class of cortical neurons that, during depolarization by current injection, intrinsically generate bursts of high-frequency action potentials with an interburst frequency between 30 and 50 Hz. In the present study, we show for the first time that FRB cells in the primary visual cortex can be either simple or complex and are distributed throughout all cortical layers. Strikingly, both simple and complex FRB cells generate spike bursts at gamma frequencies in response to depolarizing current pulses, but only simple FRB cells exhibit a selective, stimulus feature-dependent increase in gamma oscillations in response to visual stimulation. In addition, we find that hyperpolarization does not reduce the relative power of visually evoked gamma oscillations in the V(m) response of FRB cells. Our results thus indicate that visually evoked gamma activity in individual simple and complex FRB cells is generated in large part by rhythmic synaptic input, rather than by depolarization-dependent activation of intrinsic properties. Finally, the presence of FRB cells in layer 6 suggests a role for corticothalamic feedback in potentiating thalamic oscillations and facilitating the generation of a corticothalamocortical oscillatory loop. We propose that rather than functioning as pacemakers, FRB cells amplify and distribute stimulus-driven gamma oscillations in the neocortex.

Chemopreventive drug treatment in subjects with genetic predisposition to cancer: prescriber liability and healthcare disparities.

Advancements in pharmacogenomics and chemoprevention promise to reduce cancer incidence and mortality, but utilization will undoubtedly be accompanied with ethical and legal issues that largely remain unexplored or discussed. As pharmacogenomic information is assessed more comprehensively and inexpensively, it will influence decisions regarding when and to whom chemoprevention therapy will be initiated. Pharmacogenomics will change the manner in which the liability system will perceive and analyse risks. Management of the risks related to chemopreventive treatment will differ from traditional disease management. Knowledge about cancer susceptibility will need to consider environmental factors as they relate to healthcare disparities.

Response to contrast of electrophysiologically defined cell classes in primary visual cortex.

Information processing in the visual cortex is critically dependent on the input-output relationships of its component neurons. The transformation of synaptic inputs into spike trains depends in turn on the host of intrinsic membrane properties expressed by neurons, which define established electrophysiological cell classes in the neocortex. Here we studied, with intracellular recordings in vivo, how the electrophysiological cell classes in the primary visual cortex transform an increasing input, represented by stimulus contrast, into membrane depolarization and trains of action potentials. We used contrast as input because, regardless of their stimulus selectivity, primary visual cortical cells increase their firing rates in response to increases in luminance contrast. We found that both the spike rate response and the membrane potential response are best described by the hyperbolic ratio function when compared with linear, power, and logarithmic functions. In addition, both responses show similar parameter values and similar residual variance from the fits to all four functions. We also found that changes in membrane potential are similar, but firing rates differ strongly, between the established electrophysiological cell classes: fast spiking neurons show the highest firing rates, followed by fast rhythmic bursting, and regular spiking (RS) cells. In addition, among complex cells, RS cells from supragranular layers fired at higher rates than RS cells from infragranular layers. Finally, we show that the differences in firing rates between cell classes arise from differences in the slope of the relationship between membrane potential and spike rate.

Visual detection deficits following inactivation of the superior colliculus in the cat.

Lesion or inactivation of the superior colliculus (SC) of the cat results in an animal that fails to orient toward peripheral visual stimuli which normally evoke a brisk, reflexive orienting response. A failure to orient toward a visual stimulus could be the result of a sensory impairment (a failure to detect the visual stimulus) or a motor impairment (an inability to generate the orienting response). Either mechanism could explain the deficit observed during SC inactivation since neurons in the SC can carry visual sensory signals as well as motor commands involved in the generation of head and eye movements. We investigated the effects of SC inactivation in the cat in two ways. First, we tested cats in a visual detection task that required the animals to press a central, stationary foot pedal to indicate detection of a peripheral visual stimulus. Such a motor response does not involve any components of the orienting response and is unlikely to depend on SC motor commands. A deficit in this task would indicate that the SC plays an important role in the detection of visual targets even in a task that does not require visual orienting. Second, to further investigate the visual orienting deficit observed during SC inactivation and to make direct comparisons between detection and orienting performance, we tested cats in a standard perimetry paradigm. Performance in both tasks was tested following focal inactivation of the SC with microinjections of muscimol at various depths and rostral/caudal locations throughout the SC. Our results reveal a dramatic deficit in both the visual detection task and the visual orienting task following inactivation of the SC with muscimol.

Effects of surround motion on receptive-field gain and structure in area 17 of the cat.

Modulation of responses elicited by moving bars within the classical receptive fields (CRF) of cat area 17 neurons were studied as a function of the direction and velocity of drifting gratings in the surrounds. Several different types of modulation were observed; collectively, the responses of most cells, both simple and complex, were strongly modulated by surround motion. None of these cells appear to signal relative velocity between the CRF and its surround. The gain and spatiotemporal structure of the CRF mechanism were estimated using contrast-response functions and reverse correlation with spatiotemporal ternary white noise, respectively. These measurements were made in the presence of surround gratings shown to significantly modify responses elicited from the CRF. In all cases, the gain of the CRF mechanism was driven up or down relative to controls but the receptive-field structure did not change in any way. We conclude that neurons in cat area 17 act like scalable filters, meaning that their gains can be adjusted by stimuli in the surrounds without altering the properties of the CRF. This was verified by showing that velocity tuning curves were also unmodified by stimuli in the surround that did change the gain. Based in part on these data, we discuss the notion that primary visual cortex makes use of a double-opponent mechanism for the representation of local discontinuities in motion and orientation.