Kelsey L. Clark

Probing neural circuitry and function with electrical microstimulation

Since the discovery of the nervous systems electrical excitability more than 200 years ago, neuroscientists have used electrical stimulation to manipulate brain activity in order to study its function. Microstimulation has been a valuable technique for probing neural circuitry and identifying networks of neurons that underlie perception, movement and cognition. In this review, we focus on the use of stimulation in behaving primates, an experimental system that permits causal inferences to be made about the effect of stimulation-induced activity on the resulting behaviour or neural signals elsewhere in the brain.

Complex interactions amongst N-cadherin, DLAR, and Liprin-α regulate Drosophila photoreceptor axon targeting

The formation of stable adhesive contacts between pre- and post-synaptic neurons represents the initial step in synapse assembly. The cell adhesion molecule N-cadherin, the receptor tyrosine phosphatase DLAR, and the scaffolding molecule Liprin-alpha play critical, evolutionarily conserved roles in this process. However, how these proteins signal to the growth cone and are themselves regulated remains poorly understood. Using Drosophila photoreceptors (R cells) as a model, we evaluate genetic and physical interactions among these three proteins. We demonstrate that DLAR function in this context is independent of phosphatase activity but requires interactions mediated by its intracellular domain. Genetic studies reveal both positive and, surprisingly, inhibitory interactions amongst all three genes. These observations are corroborated by biochemical studies demonstrating that DLAR physically associates via its phosphatase domain with N-cadherin in Drosophila embryos. Together, these data demonstrate that N-cadherin, DLAR, and Liprin-alpha function in a complex to regulate adhesive interactions between pre- and post-synaptic cells and provide a novel mechanism for controlling the activity of Liprin-alpha in the developing growth cone.

The role of prefrontal catecholamines in attention and working memory

While much progress has been made in identifying the brain regions and neurochemical systems involved in the cognitive processes disrupted in mental illnesses, to date, the level of detail at which neurobiologists can describe the chain of events giving rise to cognitive functions is very rudimentary. Much of the intense interest in understanding cognitive functions is motivated by the hope that it might be possible to understand these complex functions at the level of neurons and neural circuits. Here, we review the current state of the literature regarding how modulations in catecholamine levels within the prefrontal cortex (PFC) alter the neuronal and behavioral correlates of cognitive functions, particularly attention and working memory.

Visual attention: Linking prefrontal sources to neuronal and behavioral correlates.

Attention is a means of flexibly selecting and enhancing a subset of sensory input based on the current behavioral goals. Numerous signatures of attention have been identified throughout the brain, and now experimenters are seeking to determine which of these signatures are causally related to the behavioral benefits of attention, and the source of these modulations within the brain. Here, we review the neural signatures of attention throughout the brain, their theoretical benefits for visual processing, and their experimental correlations with behavioral performance. We discuss the importance of measuring cue benefits as a way to distinguish between impairments on an attention task, which may instead be visual or motor impairments, and true attentional deficits. We examine evidence for various areas proposed as sources of attentional modulation within the brain, with a focus on the prefrontal cortex. Lastly, we look at studies that aim to link sources of attention to its neuronal signatures elsewhere in the brain.

Persistent Spatial Information in the Frontal Eye Field during Object-Based Short-Term Memory

Spatial attention is known to gate entry into visual short-term memory, and some evidence suggests that spatial signals may also play a role in binding features or protecting object representations during memory maintenance. To examine the persistence of spatial signals during object short-term memory, the activity of neurons in the frontal eye field (FEF) of macaque monkeys was recorded during an object-based delayed match-to-sample task. In this task, monkeys were trained to remember an object image over a brief delay, regardless of the locations of the sample or target presentation. FEF neurons exhibited visual, delay, and target period activity, including selectivity for sample location and target location. Delay period activity represented the sample location throughout the delay, despite the irrelevance of spatial information for successful task completion. Furthermore, neurons continued to encode sample position in a variant of the task in which the matching stimulus never appeared in their response field, confirming that FEF maintains sample location independent of subsequent behavioral relevance. FEF neurons also exhibited target-position-dependent anticipatory activity immediately before target onset, suggesting that monkeys predicted target position within blocks. These results show that FEF neurons maintain spatial information during short-term memory, even when that information is irrelevant for task performance.

Spatial working memory alters the efficacy of input to visual cortex

Prefrontal cortex modulates sensory signals in extrastriate visual cortex, in part via its direct projections from the frontal eye field (FEF), an area involved in selective attention. We find that working memory-related activity is a dominant signal within FEF input to visual cortex. Although this signal alone does not evoke spiking responses in areas V4 and MT during memory, the gain of visual responses in these areas increases, and neuronal receptive fields expand and shift towards the remembered location, improving the stimulus representation by neuronal populations. These results provide a basis for enhancing the representation of working memory targets and implicate persistent FEF activity as a basis for the interdependence of working memory and selective attention.

A Distinct Contribution of the Frontal Eye Field to the Visual Representation of Saccadic Targets

The responses of neurons within posterior visual cortex are enhanced when response field (RF) stimuli are targeted with saccadic eye movements. Although the motor-related activity within oculomotor structures seems a likely source of the enhancement, the origin of the modulation is unknown. We tested the role of the frontal eye field (FEF) in driving presaccadic modulation in area V4 by inactivating FEF neurons at retinotopically corresponding sites within the macaque monkey (Macaca mulatta) brain. As previously observed, FEF inactivation produced profound, and spatially specific, deficits in memory-guided saccades, and increased the latency, scatter, and duration of visually guided saccades. Despite the clear behavioral deficits, we found that rather than being eliminated or reduced by FEF inactivation, presaccadic enhancement of V4 activity was increased. FEF inactivation nonetheless diminished the stimulus discriminability of V4 visual responses both during fixation and in the presaccadic period. Thus, without input from the FEF, V4 neurons signaled more about the direction of saccades and less about the features of the saccadic target. In addition, FEF inactivation significantly increased the suppressive effects of non-RF stimuli on V4 activity. These results reveal multiple sources of presaccadic modulation in V4 and suggest that the FEF contributes uniquely to the presaccadic specification of visual target features.

Copula Regression Analysis of Simultaneously Recorded Frontal Eye Field and Inferotemporal Spiking Activity during Object-Based Working Memory

Inferotemporal (IT) neurons are known to exhibit persistent, stimulus-selective activity during the delay period of object-based working memory tasks. Frontal eye field (FEF) neurons show robust, spatially selective delay period activity during memory-guided saccade tasks. We present a copula regression paradigm to examine neural interaction of these two types of signals between areas IT and FEF of the monkey during a working memory task. This paradigm is based on copula models that can account for both marginal distribution over spiking activity of individual neurons within each area and joint distribution over ensemble activity of neurons between areas. Considering the popular GLMs as marginal models, we developed a general and flexible likelihood framework that uses the copula to integrate separate GLMs into a joint regression analysis. Such joint analysis essentially leads to a multivariate analog of the marginal GLM theory and hence efficient model estimation. In addition, we show that Granger causality between spike trains can be readily assessed via the likelihood ratio statistic. The performance of this method is validated by extensive simulations, and compared favorably to the widely used GLMs. When applied to spiking activity of simultaneously recorded FEF and IT neurons during working memory task, we observed significant Granger causality influence from FEF to IT, but not in the opposite direction, suggesting the role of the FEF in the selection and retention of visual information during working memory. The copula model has the potential to provide unique neurophysiological insights about network properties of the brain.

Stimulus context alters neural representations of faces in inferotemporal cortex

One goal of our nervous system is to form predictions about the world around us to facilitate our responses to upcoming events. One basis for such predictions could be the recently encountered visual stimuli, or the recent statistics of the visual environment. We examined the effect of recently experienced stimulus statistics on the visual representation of face stimuli by recording the responses of face-responsive neurons in the final stage of visual object recognition, the inferotemporal (IT) cortex, during blocks in which the probability of seeing a particular face was either 100% or only 12%. During the block with only face images, ∼30% of IT neurons exhibit enhanced anticipatory activity before the evoked visual response. This anticipatory modulation is followed by greater activity, broader view tuning, more distributed processing, and more reliable responses of IT neurons to the face stimuli. These changes in the visual response were sufficient to improve the ability of IT neurons to represent a variable property of the predictable face images (viewing angle), as measured by the performance of a simple linear classifier. These results demonstrate that the recent statistics of the visual environment can facilitate processing of stimulus information in the population neuronal representation. NEW & NOTEWORTHY Neurons in inferotemporal (IT) cortex anticipate the arrival of a predictable stimulus, and visual responses to an expected stimulus are more distributed throughout the population of IT neurons, providing an enhanced representation of second-order stimulus information (in this case, viewing angle). The findings reveal a potential neural basis for the behavioral benefits of contextual expectation.

Persistent spatial information in the fef during object-based short-term memory does not contribute to task performance

We previously reported the existence of a persistent spatial signal in the FEF during object-based STM. This persistent activity reflected the location at which the sample appeared, irrespective of the location of upcoming targets. We hypothesized that such a spatial signal could be used to maintain or enhance object-selective memory activity elsewhere in cortex, analogous to the role of a spatial signal during attention. Here, we inactivated a portion of the FEF with GABAa agonist muscimol to test whether the observed activity contributes to object memory performance. We found that, although RTs were slowed for saccades into the inactivated portion of retinotopic space, performance for samples appearing in that region was unimpaired. This contrasts with the devastating effects of the same FEF inactivation on purely spatial working memory, as assessed with the memory-guided saccade task. Thus, in a task in which a significant fraction of FEF neurons displayed persistent, sample location-based activity, disrupting this activity had no impact on task performance.