Anatomical and functional study of the cuneiform nucleus: A critical site to organize innate defensive behaviors.

The cuneiform nucleus (CUN) is a midbrain structure located lateral to the caudal part of the periaqueductal gray. In the present investigation, we first performed a systematic analysis of the afferent and efferent projections of the CUN using FluoroGold and Phaseolus vulgaris leucoagglutinin as retrograde and anterograde neuronal tracers, respectively. Next, we examined the behavioral responses to optogenetic activation of the CUN and evaluated the impact of pharmacological inactivation of the CUN in both innate and contextual fear responses to a predatory threat (i.e., a live cat). The present hodologic evidence indicates that the CUN might be viewed as a caudal component of the periaqueductal gray. The CUN has strong bidirectional links with the dorsolateral periaqueductal gray (PAGdl). Our hodological findings revealed that the CUN and PAGdl share a similar source of inputs involved in integrating information related to life-threatening events and that the CUN provides particularly strong projections to brain sites influencing antipredatory defensive behaviors. Our functional studies revealed that the CUN mediates innate freezing and flight antipredatory responses but does not seem to influence the acquisition and expression of learned fear responses.

Dynamics in brain activation and behaviour in acute and repeated social defensive behaviour.

In nature, confrontations between conspecifics are recurrent and related, in general, due to the lack of resources such as food and territory. Adequate defence against a conspecific aggressor is essential for the individual's survival and the group integrity. However, repeated social defeat is a significant stressor promoting several behavioural changes, including social defence per se. What would be the neural basis of these behavioural changes? To build new hypotheses about this, we here investigate the effects of repeated social stress on the neural circuitry underlying motivated social defence behaviour in male mice. We observed that animals re-exposed to the aggressor three times spent more time in passive defence during the last exposure than in the first one. These animals also show less activation of the amygdalar and hypothalamic nuclei related to the processing of conspecific cues. In turn, we found no changes in the activation of the hypothalamic dorsal pre-mammillary nucleus (PMD) that is essential for passive defence. Therefore, our data suggest that the balance between the activity of circuits related to conspecific processing and the PMD determines the pattern of social defence behaviour. Changes in this balance may be the basis of the adaptations in social defence after repeated social defeat.

Evidence of a Role for the Lateral Hypothalamic Area Juxtadorsomedial Region (LHAjd) in Defensive Behaviors Associated with Social Defeat.

Our understanding of the extrinsic connections of the lateral hypothalamic area (LHA) has deepened in recent years. In particular, a series of studies using neural pathway-tracing methods to investigate the macroconnections of histologically differentiated LHA regions, have revealed that the neural connections of these regions are substantially distinct, and have robust connections with neural circuits controlling survival behaviors. To begin testing functional associations suggested by the distinct LHA region neural connections, the present study has investigated the role of the LHA juxtadorsomedial region (LHAjd) in the control of social defeat (a socially-relevant defensive behavior). Male rats received bilateral cytotoxic lesions targeted to the LHAjd. A resident-intruder paradigm was then employed to investigate the effect of these lesions on defensive behavioral responses. Behavioral data were collected during three phases of testing: (1) pre-encounter habituation to testing context; (2) encounter with a dominant conspecific in the testing context; and (3) post-encounter context. Statistical analysis of behavioral measures revealed a significant decrease in risk assessment behaviors during post-encounter context testing in lesioned intruders compared to sham-lesioned and intact rats. However, changes in defensive behavioral measures during the habituation, or during resident-intruder encounters, did not reach significance. We discuss these data in relation to LHAjd (and neighboring LHA region) neural connections, and in relation to current advances in understanding of the neural control of defensive behaviors. A refined model for the neural circuits that are central to the control of socially-relevant defensive behaviors is outlined. We also consider possible broader implications of these data for disorders of behavioral control.

Computational models of the Posner simple and choice reaction time tasks.

The landmark experiments by Posner in the late 1970s have shown that reaction time (RT) is faster when the stimulus appears in an expected location, as indicated by a cue; since then, the so-called Posner task has been considered a "gold standard" test of spatial attention. It is thus fundamental to understand the neural mechanisms involved in performing it. To this end, we have developed a Bayesian detection system and small integrate-and-fire neural networks, which modeled sensory and motor circuits, respectively, and optimized them to perform the Posner task under different cue type proportions and noise levels. In doing so, main findings of experimental research on RT were replicated: the relative frequency effect, suboptimal RTs and significant error rates due to noise and invalid cues, slower RT for choice RT tasks than for simple RT tasks, fastest RTs for valid cues and slowest RTs for invalid cues. Analysis of the optimized systems revealed that the employed mechanisms were consistent with related findings in neurophysiology. Our models predict that (1) the results of a Posner task may be affected by the relative frequency of valid and neutral trials, (2) in simple RT tasks, input from multiple locations are added together to compose a stronger signal, and (3) the cue affects motor circuits more strongly in choice RT tasks than in simple RT tasks. In discussing the computational demands of the Posner task, attention has often been described as a filter that protects the nervous system, whose capacity is limited, from information overload. Our models, however, reveal that the main problems that must be overcome to perform the Posner task effectively are distinguishing signal from external noise and selecting the appropriate response in the presence of internal noise.

Bias and learning in temporal binding: intervals between actions and outcomes are compressed by prior bias.

It has consistently been shown that agents judge the intervals between their actions and outcomes as compressed in time, an effect named intentional binding. In the present work, we investigated whether this effect is result of prior bias volunteers have about the timing of the consequences of their actions, or if it is due to learning that occurs during the experimental session. Volunteers made temporal estimates of the interval between their action and target onset (Action conditions), or between two events (No-Action conditions). Our results show that temporal estimates become shorter throughout each experimental block in both conditions. Moreover, we found that observers judged intervals between action and outcomes as shorter even in very early trials of each block. To quantify the decrease of temporal judgments in experimental blocks, exponential functions were fitted to participants' temporal judgments. The fitted parameters suggest that observers had different prior biases as to intervals between events in which action was involved. These findings suggest that prior bias might play a more important role in this effect than calibration-type learning processes.

Ventral premammillary nucleus as a critical sensory relay to the maternal aggression network.

Maternal aggression is under the control of a wide variety of factors that prime the females for aggression or trigger the aggressive event. Maternal attacks are triggered by the perception of sensory cues from the intruder, and here we have identified a site in the hypothalamus of lactating rats that is highly responsive to the male intruder--the ventral premammillary nucleus (PMv). The PMv is heavily targeted by the medial amygdalar nucleus, and we used lesion and immediate-early gene studies to test our working hypothesis that the PMv signals the presence of a male intruder and transfers this information to the network organizing maternal aggression. PMv-lesioned dams exhibit significantly reduced maternal aggression, without affecting maternal care. The Fos analysis revealed that PMv influences the activation of hypothalamic and septal sites shown to be mobilized during maternal aggression, including the medial preoptic nucleus (likely to represent an important locus to integrate priming stimuli critical for maternal aggression), the caudal two-thirds of the hypothalamic attack area (comprising the ventrolateral part of the ventromedial hypothalamic nucleus and the adjacent tuberal region of the lateral hypothalamic area, critical for the expression of maternal aggression), and the ventral part of the anterior bed nuclei of the stria terminalis (presently discussed as being involved in controlling neuroendocrine and autonomic responses accompanying maternal aggression). These findings reveal an important role for the PMv in detecting the male intruder and how this nucleus modulates the network controlling maternal aggression.

The relation between action, predictability and temporal contiguity in temporal binding.

Previous studies have documented a subjective temporal attraction between actions and their effects. This finding, named intentional binding, is thought to be the result of a cognitive function that links actions to their consequences. Although several studies have tried to outline the necessary and sufficient conditions for intentional binding, a quantitative comparison between the roles of temporal contiguity, predictability and voluntary action and the evaluation of their interactions is difficult due to the high variability of the temporal binding measurements. In the present study, we used a novel methodology to investigate the properties of intentional binding. Subjects judged whether an auditory stimulus, which could either be triggered by a voluntary finger lift or be presented after a visual temporal marker unrelated to any action, was presented synchronously with a reference stimulus. In three experiments, the predictability, the interval between action and consequence and the presence of action itself were manipulated. The results indicate that (1) action is a necessary condition for temporal binding; (2) a fixed interval between the two events is not sufficient to cause the effect and (3) only in the presence of voluntary action do temporal predictability and contiguity play a significant role in modulating the effect.These findings are discussed in the context of the relationship between intentional binding and temporal expectation.

Voluntary action and causality in temporal binding.

Previous studies have documented temporal attraction in perceived times of actions and their effects. While some authors argue that voluntary action is a necessary condition for this phenomenon, others claim that the causal relationship between action and effect is the crucial ingredient. In the present study, we investigate voluntary action and causality as the necessary and sufficient conditions for temporal binding. We used a variation of the launching effect proposed by Michotte, in which participants controlled the launch stimulus in some blocks. Volunteers reported causality ratings and estimated the interval between the two events. Our results show dissociations between causality ratings and temporal estimation. While causality ratings are not affected by voluntary action, temporal bindings were only found in the presence of both voluntary action and high causality. Our results indicate that voluntary action and causality are both necessary for the emergence of temporal binding.

Dissecting the brain's fear system reveals the hypothalamus is critical for responding in subordinate conspecific intruders.

Effective defense against natural threats in the environment is essential for the survival of individual animals. Thus, instinctive behavioral responses accompanied by fear have evolved to protect individuals from predators and from opponents of the same species (dominant conspecifics). While it has been suggested that all perceived environmental threats trigger the same set of innately determined defensive responses, we tested the alternate hypothesis that different stimuli may evoke differentiable behaviors supported by distinct neural circuitry. The results of behavioral, neuronal immediate early gene activation, lesion, and neuroanatomical experiments indicate that the hypothalamus is necessary for full expression of defensive behavioral responses in a subordinate conspecific, that lesions of the dorsal premammillary nucleus drastically reduce behavioral measures of fear in these animals, and that essentially separate hypothalamic circuitry supports defensive responses to a predator or a dominant conspecific. It is now clear that differentiable neural circuitry underlies defensive responses to fear conditioning associated with painful stimuli, predators, and dominant conspecifics and that the hypothalamus is an essential component of the circuitry for the latter two stimuli.

A psychophysical and computational analysis of the spatio-temporal mechanisms underlying the flash-lag effect.

Several accounts put forth to explain the flash-lag effect (FLE) rely mainly on either spatial or temporal mechanisms. Here we investigated the relationship between these mechanisms by psychophysical and theoretical approaches. In a first experiment we assessed the magnitudes of the FLE and temporal-order judgments performed under identical visual stimulation. The results were interpreted by means of simulations of an artificial neural network, that was also employed to make predictions concerning the FLE. The model predicted that a spatio-temporal mislocalisation would emerge from two, continuous and abrupt-onset, moving stimuli. Additionally, a straightforward prediction of the model revealed that the magnitude of this mislocalisation should be task-dependent, increasing when the use of the abrupt-onset moving stimulus switches from a temporal marker only to both temporal and spatial markers. Our findings confirmed the model's predictions and point to an indissoluble interplay between spatial facilitation and processing delays in the FLE.

Computational neurobiology of the flash-lag effect.

In the flash-lag effect (FLE) a moving object is perceived ahead of a stationary stimulus flashed in spatial alignment. Several explanations have been proposed to account for the FLE and its dependence on a variety of psychophysical attributes. Here, we show that a simple feed-forward network reproduces the standard FLE and several related manifestations, such as its modulation by stimulus luminance, trajectory, priming, and spatial predictability. A minimal set of elements, based on plausible neuronal mechanisms, yields a unified account of these visual illusions and possibly other perceptual phenomena.

The generators of slow potentials obtained during verbal, pictorial and spatial tasks.

The purpose of this study was to test whether slow cortical electrical activity is specific to performance on verbal, pictorial and spatial tasks. Twenty-nine healthy subjects were required to compare pairs of visual stimuli separated by a delay of 2.5 s in a S1-S2 contingent negative variation-type paradigm. Slow potentials (SPs) were recorded by high-resolution EEG (123 channels) and their generators modeled by current density reconstruction using individual MRIs as source space models. Activity in each architectonic area of Brodmann was scored with respect to individual maximum current by a percentile method. Results showed a multifocal pattern of current density foci comprising the SP generators, including frontal and posterior cortices in all subjects, with the most active areas being common to the three tasks. In spite of the intersubject variability in the sets of active areas for each given task, a few cortical areas were observed to discriminate between tasks in a statistically significant way: the verbal task corresponded to stronger electrical activity in right area 45 than the other tasks; the spatial to weaker activity in right area 38 and left area 5 than the other tasks; the pictorial, compared to the spatial task, to stronger activity in left area 39; the verbal, compared to the spatial task, to stronger activity in left area 10, and compared to the pictorial, to weaker activity in right area 20. The present method of SP analysis may aid in the functional mapping of human association cortices in individual cases. We discuss our results emphasizing intersubject variability in cortical activity patterns and the possibility of finding more universal patterns.

Evidence for an attentional component of the perceptual misalignment between moving and flashing stimuli.

If a pair of dots, diametrically opposed to each other, is flashed in perfect alignment with another pair of dots rotating about the visual fixation point, most observers perceive the rotating dots as being ahead of the flashing dots (flash-lag effect). This psychophysical effect was first interpreted as the result of a perceptual extrapolation of the position of the moving dots. Also, it has been conceived as the result of differential visual latencies between flashing and moving stimuli, arising from purely sensory factors and/or expressing the contribution of attentional mechanisms as well. In a series of two experiments, we had observers judge the relative position between rotating and static dots at the moment a temporal marker was presented in the visual field. In experiment 1 we manipulated the nature of the temporal marker used to prompt the alignment judgment. This resulted in three main findings: (i) the flash-lag effect was observed to depend on the visual eccentricity of the flashing dots; (ii) the magnitude of the flash-lag effect was not dependent on the offset of the flashing dot; and (iii) the moving stimulus, when suddenly turned off, was perceived as lagging behind its disappearance location. Taken altogether, these results suggest that neither visible persistence nor motion extrapolation can account for the perceptual flash-lag phenomenon. The participation of attentional mechanisms was investigated in experiment 2, where the magnitude of the flash-lag effect was measured under both higher and lower predictability of the location of the flashing dot. Since the magnitude of the flash-lag effect significantly increased with decreasing predictability, we conclude that the observer's attentional set can modulate the differential latencies determining this perceptual effect. The flash-lag phenomenon can thus be conceived as arising from differential visual latencies which are determined not only by the physical attributes of the stimulus, such as its luminance or eccentricity, but also by attentional mechanisms influencing the delays involved in the perceptual processing.