Ratphones: An Affordable Tool for Highly Controlled Sound Presentation in Freely Moving Rats.

Encoding and processing sensory information is key to understanding the environment and to guiding behavior accordingly. Characterizing the behavioral and neural correlates of these processes requires the experimenter to have a high degree of control over stimuli presentation. For auditory stimulation in animals with relatively large heads, this can be accomplished by using headphones. However, it has proven more challenging in smaller species, such as rats and mice, and has been only partially solved using closed-field speakers in anesthetized or head-restrained preparations. To overcome the limitations of such preparations and to deliver sound with high precision to freely moving animals, we have developed a set of miniature headphones for rats. The headphones consist of a small, skull-implantable base attached with magnets to a fully adjustable structure that holds the speakers and keeps them in the same position with respect to the ears.

The cold-sensing ion channel TRPM8 regulates central and peripheral clockwork and the circadian oscillations of body temperature.

AIM: Physiological functions in mammals show circadian oscillations, synchronized by daily cycles of light and temperature. Central and peripheral clocks participate in this regulation. Since the ion channel TRPM8 is a critical cold sensor, we investigated its role in circadian function. METHODS: We used TRPM8 reporter mouse lines and TRPM8-deficient mice. mRNA levels were determined by in situ hybridization or RT-qPCR and protein levels by immunofluorescence. A telemetry system was used to measure core body temperature (Tc). RESULTS: TRPM8 is expressed in the retina, specifically in cholinergic amacrine interneurons and in a subset of melanopsin-positive ganglion cells which project to the central pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. TRPM8-positive fibres were also found innervating choroid and ciliary body vasculature, with a putative function in intraocular temperature, as shown in TRPM8-deficient mice. Interestingly, Trpm8-/- animals displayed increased expression of the clock gene Per2 and vasopressin (AVP) in the SCN, suggesting a regulatory role of TRPM8 on the central oscillator. Since SCN AVP neurons control body temperature, we studied Tc in driven and free-running conditions. TRPM8-deficiency increased the amplitude of Tc oscillations and, under dim constant light, induced a greater phase delay and instability of Tc rhythmicity. Finally, TRPM8-positive fibres innervate peripheral organs, like liver and white adipose tissue. Notably, Trpm8-/- mice displayed a dysregulated expression of Per2 mRNA in these metabolic tissues. CONCLUSION: Our findings support a function of TRPM8 as a temperature sensor involved in the regulation of central and peripheral clocks and the circadian control of Tc.

Hyperthermia-Induced Changes in EEG of Anesthetized Mice Subjected to Passive Heat Exposure.

Currently, the role of hypothermia in electroencephalography (EEG) is well-established. However, few studies have investigated the effect of hyperthermia on EEG, an important physiological parameter governing brain function. The aim of this work was to determine how neuronal activity in anesthetized mice is affected when the temperature rises above the physiological threshold mandatory to maintain the normal body functions. In this study, a temperature-elevation protocol, from 37 to 42°C, was applied to four female mice of 2-3 months old while EEG was recorded simultaneously. We found that hyperthermia reduces EEG amplitude by 4.36% when rising from 37 to 38 degrees and by 24.33% when it is increased to 42 degrees. Likewise, increasing the body temperature produces a very large impact on the EEG spectral parameters, reducing the frequency power at the delta, theta, alpha, and beta bands. Our results show that hyperthermia has a global effect on the EEG, being able to change the electrical activity of the brain.

The mechanistic foundation of Weber's law.

Although Weber's law is the most firmly established regularity in sensation, no principled way has been identified to choose between its many proposed explanations. We investigated Weber's law by training rats to discriminate the relative intensity of sounds at the two ears at various absolute levels. These experiments revealed the existence of a psychophysical regularity, which we term time-intensity equivalence in discrimination (TIED), describing how reaction times change as a function of absolute level. The TIED enables the mathematical specification of the computational basis of Weber's law, placing strict requirements on how stimulus intensity is encoded in the stochastic activity of sensory neurons and revealing that discriminative choices must be based on bounded exact accumulation of evidence. We further demonstrate that this mechanism is not only necessary for the TIED to hold but is also sufficient to provide a virtually complete quantitative description of the behavior of the rats.

State-dependent geometry of population activity in rat auditory cortex.

The accuracy of the neural code depends on the relative embedding of signal and noise in the activity of neural populations. Despite a wealth of theoretical work on population codes, there are few empirical characterizations of the high-dimensional signal and noise subspaces. We studied the geometry of population codes in the rat auditory cortex across brain states along the activation-inactivation continuum, using sounds varying in difference and mean level across the ears. As the cortex becomes more activated, single-hemisphere populations go from preferring contralateral loud sounds to a symmetric preference across lateralizations and intensities, gain-modulation effectively disappears, and the signal and noise subspaces become approximately orthogonal to each other and to the direction corresponding to global activity modulations. Level-invariant decoding of sound lateralization also becomes possible in the active state. Our results provide an empirical foundation for the geometry and state-dependence of cortical population codes.

Using experience to improve: how errors shape behavior and brain activity in monkeys.

Previous works have shown that neurons from the ventral premotor cortex (PMv) represent several elements of perceptual decisions. One of the most striking findings was that, after the outcome of the choice is known, neurons from PMv encode all the information necessary for evaluating the decision process. These results prompted us to suggest that this cortical area could be involved in shaping future behavior. In this work, we have characterized neuronal activity and behavioral performance as a function of the outcome of the previous trial. We found that the outcome of the immediately previous trial (n-1) significantly changes, in the current trial (n), the activity of single cells and behavioral performance. The outcome of trial n-2, however, does not affect either behavior or neuronal activity. Moreover, the outcome of difficult trials had a greater impact on performance and recruited more PMv neurons than the outcome of easy trials. These results give strong support to our suggestion that PMv neurons evaluate the decision process and use this information to modify future behavior.

Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice.

The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8-/- mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30°C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. Trpm8-/- mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity.SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.

Representing the consequences of our actions trial by trial: Complex and flexible encoding of feedback valence and magnitude.

In the last decades it has been shown that two components of the event-related potentials (ERPs), the feedback-related negativity (FRN) and the P300, reflect the evaluation of the outcomes of a given course of action. Within the reinforcement learning theory, the prevailing interpretation of the relationship between FRN and P300 is the classical "independent coding model". This model proposes that the FRN is only sensitive to feedback valence whereas the P300 is only sensitive to feedback magnitude. However, these predictions have recently been challenged and the question remains unsolved. The goal of the present study is to shed light on the effects of outcome valence and magnitude on the FRN and the feedback-P300. The electroencephalographic (EEG) activity was recorded while participants performed a perceptual discrimination task with two levels of difficulty, in which they could receive large or small rewards and penalties. We used receiver operating characteristics (ROC) analyses, which allowed us to analyze the relationship between the outcomes and EEG on a trial-by-trial basis. The results reveal that both components, which are contingent on feedback presentation, are sensitive to outcome valence. Regarding magnitude, this only affects the feedback P300, and only in conjunction with difficulty. Finally, we found that task difficulty has the opposite effect on these components, both in their latencies and discriminability. Our results suggest that the FRN and the feedback-P300 in fact reflect different performance monitoring processes in a flexible way that depends on the behavioral context.

The Encoding of Decision Difficulty and Movement Time in the Primate Premotor Cortex.

Estimating the difficulty of a decision is a fundamental process to elaborate complex and adaptive behaviour. In this paper, we show that the movement time of behaving monkeys performing a decision-making task is correlated with decision difficulty and that the activity of a population of neurons in ventral Premotor cortex correlates with the movement time. Moreover, we found another population of neurons that encodes the discriminability of the stimulus, thereby supplying another source of information about the difficulty of the decision. The activity of neurons encoding the difficulty can be produced by very different computations. Therefore, we show that decision difficulty can be encoded through three different mechanisms: 1. Switch time coding, 2. rate coding and 3. binary coding. This rich representation reflects the basis of different functional aspects of difficulty in the making of a decision and the possible role of difficulty estimation in complex decision scenarios.

Bases neurales de las decisiones perceptivas: papel de la corteza premotora ventral / Neural correlates of perceptual decisions: the role of the ventral premotor cortex

A pesar de que inicialmente se consideró la corteza premotora como el sustrato de funciones puramente motoras, pronto se vio que está implicada en procesos cognitivos de alto nivel. El uso combinado de tareas conductuales y registros electrofi siológicos ha permitido importantes avances en la comprensión y descripción funcional de esta área. El patrón de conexiones de la corteza premotora ventral la sitúa en una posición privilegiada para participar en las decisiones perceptivas, en las que la información sensorial se combina con las expectativas y el conocimiento previo para alcanzar la elección conductual. Los correlatos neuronales del proceso de decisión se han descrito en varias áreas corticales de los primates. En este trabajo describimos resultados experimentales que demuestran que las diferentes etapas de las decisiones perceptivas se codifi can en la tasa de descarga de las neuronas de la corteza premotora ventral. Esto sugiere que esta área está implicada en el uso de información sensorial, almacenada en la memoria de trabajo o recuperada de la memoria a largo plazo, para alcanzar una decisión. Además, una vez que los sujetos han comunicado la elección, las neuronas codifi can toda la información necesaria para evaluar el resultado del proceso de decisión, lo que sugiere que la corteza premotora ventral podría participar en la modifi cación del comportamiento futuro como resultado de dicha evaluación (AU)

Although the premotor cortex was initially viewed as the substrate of pure motor functions, it was soon realized that this cortical region is also involved in higher order cognitive processes. By using behavioral tasks together with electrophysiological recordings it has been possible to advance in our understanding on the functional role of this area. Given its pattern of connections, the premotor ventral cortex is well suited to participate in perceptual decisions, in which sensory information is combined with knowledge on previous outcomes and expectancies to reach a behavioral choice. The neuronal correlates of the decision process have been described in several cortical areas of primates. In this work we describe our experimental results showing that diff erent stages or elements of perceptual decisions are encoded in the fi ring rate of premotor ventral cortex neurons. This provides compelling evidence suggesting that this area is involved in the use of sensory evidence -maintained in working memory or retrieved from long-term memory- to reach a decision. Furthermore, after the behavioral response the same neurons convey all the information needed to evaluate the outcome of the choice. This suggests that the premotor ventral cortex could participate in shaping future behavior as a result of this evaluation (AU)

[Neural correlates of perceptual decisions: the role of the ventral premotor cortex]. / Bases neurales de las decisiones perceptivas: papel de la corteza premotora ventral.

Although the premotor cortex was initially viewed as the substrate of pure motor functions, it was soon realized that this cortical region is also involved in higher order cognitive processes. By using behavioral tasks together with electrophysiological recordings it has been possible to advance in our understanding on the functional role of this area. Given its pattern of connections, the premotor ventral cortex is well suited to participate in perceptual decisions, in which sensory information is combined with knowledge on previous outcomes and expectancies to reach a behavioral choice. The neuronal correlates of the decision process have been described in several cortical areas of primates. In this work we describe our experimental results showing that different stages or elements of perceptual decisions are encoded in the firing rate of premotor ventral cortex neurons. This provides compelling evidence suggesting that this area is involved in the use of sensory evidence -maintained in working memory or retrieved from long-term memory- to reach a decision. Furthermore, after the behavioral response the same neurons convey all the information needed to evaluate the outcome of the choice. This suggests that the premotor ventral cortex could participate in shaping future behavior as a result of this evaluation.

TITLE: Bases neurales de las decisiones perceptivas: papel de la corteza premotora ventral.A pesar de que inicialmente se considero la corteza premotora como el sustrato de funciones puramente motoras, pronto se vio que esta implicada en procesos cognitivos de alto nivel. El uso combinado de tareas conductuales y registros electrofisiologicos ha permitido importantes avances en la comprension y descripcion funcional de esta area. El patron de conexiones de la corteza premotora ventral la situa en una posicion privilegiada para participar en las decisiones perceptivas, en las que la informacion sensorial se combina con las expectativas y el conocimiento previo para alcanzar la eleccion conductual. Los correlatos neuronales del proceso de decision se han descrito en varias areas corticales de los primates. En este trabajo describimos resultados experimentales que demuestran que las diferentes etapas de las decisiones perceptivas se codifican en la tasa de descarga de las neuronas de la corteza premotora ventral. Esto sugiere que esta area esta implicada en el uso de informacion sensorial, almacenada en la memoria de trabajo o recuperada de la memoria a largo plazo, para alcanzar una decision. Ademas, una vez que los sujetos han comunicado la eleccion, las neuronas codifican toda la informacion necesaria para evaluar el resultado del proceso de decision, lo que sugiere que la corteza premotora ventral podria participar en la modificacion del comportamiento futuro como resultado de dicha evaluacion.

EEG activity represents the correctness of perceptual decisions trial-by-trial.

Performance monitoring is an executive function, which we depend on for detecting and evaluating the consequences of our behavior. Although event related potentials (ERPs) have revealed the existence of differences after correct and incorrect decisions, it is not known whether there is a trial-by-trial representation of the accuracy of the decision. We recorded the electroencephalographic activity (EEG) while participants performed a perceptual discrimination task, with two levels of difficulty, in which they received immediate feedback. Receiver Operating Characteristic (ROC) analyses were used to reveal two components that convey trial-by-trial representations of the correctness of the decisions. Firstly, the performance monitoring-related negativity (PM-N), a negative deflection whose amplitude is higher (more negative) after incorrect trials. Secondly, the performance monitoring-related positivity (PM-P), a positive deflection whose amplitude is higher after incorrect trials. During the time periods corresponding to these components, trials can be accurately categorized as correct or incorrect by looking at the EEG activity; this categorization is more accurate when based on the PM-P. We further show that the difficulty of the discrimination task has a different effect on each component: after easy trials the latency of the PM-N is shorter and the amplitude of the PM-P is higher than after difficult trials. Consistent with previous interpretations of performance-related ERPs, these results suggest a functional differentiation between these components. The PM-N could be related to an automatic error detection system, responsible for fast behavioral corrections of ongoing actions, while the PM-P could reflect the difference between expected and actual outcomes and be related to long-term changes in the decision process.

Working memory capacity and mental rotation: evidence for a domain-general view.

Despite the existence of numerous studies that examined the relationship between working memory capacity and performance in complex cognitive tasks, it remains unclear whether this capacity is domain specific or domain general. In addition, the available empirical evidence is somewhat contradictory. In this work we have studied the role of verbal working memory capacity in a non-verbal task--mental image rotation. If this capacity were domain specific it would be expected that high and low verbal span participants would obtain similar results in the mental rotation task. We have found that this is not the case as the high span participants performed better in terms of both speed and accuracy. Moreover, these differences depended on the processing component of the mental rotation task: the higher the processing requirements the higher the differences as a function of the working memory capacity. Therefore, the evidence presented here supports the domain general hypothesis.

Optimizing the temporal dynamics of light to human perception.

No previous research has tuned the temporal characteristics of light-emitting devices to enhance brightness perception in human vision, despite the potential for significant power savings. The role of stimulus duration on perceived contrast is unclear, due to contradiction between the models proposed by Bloch and by Broca and Sulzer over 100 years ago. We propose that the discrepancy is accounted for by the observer's "inherent expertise bias," a type of experimental bias in which the observer's life-long experience with interpreting the sensory world overcomes perceptual ambiguities and biases experimental outcomes. By controlling for this and all other known biases, we show that perceived contrast peaks at durations of 50-100 ms, and we conclude that the Broca-Sulzer effect best describes human temporal vision. We also show that the plateau in perceived brightness with stimulus duration, described by Bloch's law, is a previously uncharacterized type of temporal brightness constancy that, like classical constancy effects, serves to enhance object recognition across varied lighting conditions in natural vision-although this is a constancy effect that normalizes perception across temporal modulation conditions. A practical outcome of this study is that tuning light-emitting devices to match the temporal dynamics of the human visual system's temporal response function will result in significant power savings.

Working memory capacity and mental rotation: evidence for a domain-general view

Despite the existence of numerous studies that examined the relationship between working memory capacity and performance in complex cognitive tasks, it remains unclear whether this capacity is domain specific or domain general. In addition, the available empirical evidence is somewhat contradictory. In this work we have studied the role of verbal working memory capacity in a non-verbal task - mental image rotation. If this capacity were domain specific it would be expected that high and low verbal span participants would obtain similar results in the mental rotation task. We have found that this is not the case as the high span participants performed better in terms of both speed and accuracy. Moreover, these differences depended on the processing component of the mental rotation task: the higher the processing requirements the higher the differences as a function of the working memory capacity. Therefore, the evidence presented here supports the domain general hypothesis (AU)

A pesar de la existencia de numerosos estudios que examinaron la relación entre la capacidad de memoria de trabajo y el rendimiento en tareas cognitivas complejas, no está claro si esta capacidad es específica de dominio o de dominio general. Además, la evidencia empírica disponible es algo contradictoria. En este trabajo se estudió el papel de la capacidad de la memoria de trabajo verbal en una tarea no verbal -rotación mental de imágenes-. Si esta capacidad fuese específica de dominio se esperaría que los participantes con amplitud verbal alta y baja obtuviesen resultados similares en la tarea de rotación mental. Se encontró que esto no ocurría, ya que los participantes con amplitud alta obtenían mejores resultados en cuanto a velocidad y precisión. Por otra parte, estas diferencias dependían del componente de procesamiento de la tarea de rotación mental: cuanto mayores eran las demandas de procesamiento, mayores eran también las diferencias en función de la capacidad de memoria de trabajo. Por tanto, la evidencia que aquí se presenta apoya la hipótesis de generalidad de dominio de dicha capacidad (AU)

Decision-making in the ventral premotor cortex harbinger of action.

Although the premotor (PM) cortex was once viewed as the substrate of pure motor functions, soon it was realized that it was involved in higher brain functions. By this it is meant that the PM cortex functions would better be explained as motor set, preparation for limb movement, or sensory guidance of movement rather than solely by a fixed link to motor performance. These findings, together with a better knowledge of the PM cortex histology and hodology in human and non-human primates prompted quantitative studies of this area combining behavioral tasks with electrophysiological recordings. In addition, the exploration of the PM cortex neurons with qualitative methods also suggested its participation in higher functions. Behavioral choices frequently depend on temporal cues, which together with knowledge of previous outcomes and expectancies are combined to decide and choose a behavioral action. In decision-making the knowledge about the consequences of decisions, either correct or incorrect, is fundamental because they can be used to adapt future behavior. The neuronal correlates of a decision process have been described in several cortical areas of primates. Among them, there is evidence that the monkey ventral premotor (PMv) cortex, an anatomical and physiological well-differentiated area of the PM cortex, supports both perceptual decisions and performance monitoring. Here we review the evidence that the steps in a decision-making process are encoded in the firing rate of the PMv neurons. This provides compelling evidence suggesting that the PMv is involved in the use of recent and long-term sensory memory to decide, execute, and evaluate the outcomes of the subjects' choices.

Ventral premotor cortex neuronal activity matches perceptual decisions.

The relationship between neuronal activity and psychophysical judgments is central to understanding the brain mechanisms responsible for perceptual decisions. The ventral premotor cortex is known to be involved in representing different components of the decision-making process. In this cortical area, however, neither the neuronal ability to discriminate nor the trial-to-trial relationship between neuronal activity and behavior have been studied during visual decision-making. We recorded from single neurons while monkeys reported a decision based on the comparison of the orientation of two lines shown sequentially and separated by a delay. Analyses based on signal detection theory provided both the behavioral and neuronal sensitivities (d') and the coherence between behavioral and neuronal choices. To determine the temporal evolution of neuronal sensitivity and of coherence, the optimal size and position of the encoding windows were assessed. For a subset of neurons from the premotor ventral cortex, neuronal sensitivity was close to behavioral sensitivity and the trial-to-trial coherence between the neuronal and behavioral choices was close to 100%. By comparing these results with those obtained in a motor control task we ruled out the possibility of this activity being explained by the motor component of the task. These results suggest that activity in the ventral premotor cortex explains behavioral performance and predicts trial-to-trial subject choices.

Assessing neural activity related to decision-making through flexible odds ratio curves and their derivatives.

It is well established that neural activity is stochastically modulated over time. Therefore, direct comparisons across experimental conditions and determination of change points or maximum firing rates are not straightforward. This study sought to compare temporal firing probability curves that may vary across groups defined by different experimental conditions. Odds-ratio (OR) curves were used as a measure of comparison, and the main goal was to provide a global test to detect significant differences of such curves through the study of their derivatives. An algorithm is proposed that enables ORs based on generalized additive models, including factor-by-curve-type interactions to be flexibly estimated. Bootstrap methods were used to draw inferences from the derivatives curves, and binning techniques were applied to speed up computation in the estimation and testing processes. A simulation study was conducted to assess the validity of these bootstrap-based tests. This methodology was applied to study premotor ventral cortex neural activity associated with decision-making. The proposed statistical procedures proved very useful in revealing the neural activity correlates of decision-making in a visual discrimination task.

A role for the ventral premotor cortex beyond performance monitoring.

Depending on the circumstances, decision making requires either comparing current sensory information with that showed recently or with that recovered from long-term memory (LTM). In both cases, to learn from past decisions and adapt future ones, memories and outcomes have to be available after the report of a decision. The ventral premotor cortex (PMv) is a good candidate for integrating memory traces and outcomes because it is involved in working-memory, decision-making, and encoding the outcomes. To test this hypothesis we recorded the extracellular unit activity while monkeys performed 2 variants of a visual discrimination task. In one task, the decision was based on the comparison of the orientation of a current stimulus with that of another stimulus recently shown. In the other task, the monkeys had to compare the current orientation of the stimulus with the correct one retrieved from LTM. Here, we report that when the task required retrieval of the stimulus and its use in the following trials, the neurons continue encoding this internal representation together with the outcomes after the monkey has emitted the motor response. However, this codification did not occur when the stimulus was shown recently and updated every trial. These results suggest that the PMv activity represents the information needed to evaluate the consequences of a decision. We interpret these results as evidence that the PMv plays a role in evaluating the outcomes that can serve to learn and thus adapt future decision to environmental demands.

Application of penalized splines in analyzing neuronal data.

Neuron experiments produce high-dimensional data structures. Therefore, application of smoothing techniques in the analysis of neuronal data from electrophysiological experiments has received considerable attention of late. We investigate the use of penalized splines in the analysis of neuronal data. This is first illustrated when interested in the temporal trend of a single neuron. An approach to investigate the maximal firing rate, based on the penalizedspline model is proposed. Determination of the time of maximal firing rate is based on non-linear optimization of the objective function with the corresponding confidence intervals constructed based on the first-order derivative function. To distinguish between the curves from different experimental conditions in a moment-by-moment sense, bias adjusted simulation-based simultaneous confidence bands leading to global inference in the time domain are constructed. The bands are an extension of the approach proposed by Ruppert et al. (2003). These methods are in a second step extended towards the analysis of a population of neurons via a marginal or population-averaged model.