Motivational Salience Signal in the Basal Forebrain Is Coupled with Faster and More Precise Decision Speed

The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally believed that motivational salience increases decision speed, the quantitative relationship between motivational salience and decision speed, measured by reaction time (RT), remains unclear. Here we show that the neural correlate of motivational salience in the basal forebrain (BF), defined independently of RT, is coupled with faster and also more precise decision speed. In rats performing a reward-biased simple RT task, motivational salience was encoded by BF bursting response that occurred before RT. We found that faster RTs were tightly coupled with stronger BF motivational salience signals. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision-making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. Artificially augmenting the BF motivational salience signal via electrical stimulation led to faster and more precise RTs and supports a causal relationship. Together, these results not only describe for the first time, to our knowledge, the quantitative relationship between motivational salience and faster decision speed, they also reveal the quantitative coupling relationship between motivational salience and more precise RT. Our results further establish the existence of an early and previously unrecognized step in the decision-making process that determines both the RT speed and variability of the entire decision-making process and suggest that this novel decision step is dictated largely by the BF motivational salience signal. Finally, our study raises the hypothesis that the dysregulation of decision speed in conditions such as depression, schizophrenia, and cognitive aging may result from the functional impairment of the motivational salience signal encoded by the poorly understood noncholinergic BF neurons.     

Noncholinergic neurons in the basal forebrain: often neglected but motivationally salient

Although noncholinergic neurons in the basal forebrain are known to contribute to cognition, their response properties in behaving animals is unclear. In this issue of Neuron, Lin and Nicolelis demonstrate that these neurons represent the motivational salience of sensory stimuli and may modulate cortical processing to direct top-down attention.     

Prefrontal norepinephrine determines attribution of "high" motivational salience

Intense motivational salience attribution is considered to have a major role in the development of different psychopathologies. Numerous brain areas are involved in "normal" motivational salience attribution processes; however, it is not clear whether common or different neural mechanisms also underlie intense motivational salience attribution. To elucidate this a brain area and a neural system had to be envisaged that were involved only in motivational salience attribution to highly salient stimuli. Using intracerebral microdialysis, we found that natural stimuli induced an increase in norepinephrine release in the medial prefrontal cortex of mice proportional to their salience, and that selective prefrontal norepinephrine depletion abolished the increase of norepinephrine release in the medial prefrontal cortex induced by exposure to appetitive (palatable food) or aversive (light) stimuli independently of salience. However, selective norepinephrine depletion in the medial prefrontal cortex impaired the place conditioning induced exclusively by highly salient stimuli, thus indicating that prefrontal noradrenergic transmission determines approach or avoidance responses to both reward- and aversion-related natural stimuli only when the salience of the unconditioned natural stimulus is high enough to induce sustained norepinephrine outflow. This affirms that prefrontal noradrenergic transmission determines motivational salience attribution selectively when intense motivational salience is processed, as in conditions that characterize psychopathological outcomes.     

Expectation modulates neural responses to pleasant and aversive stimuli in primate amygdala

Animals and humans learn to approach and acquire pleasant stimuli and to avoid or defend against aversive ones. However, both pleasant and aversive stimuli can elicit arousal and attention, and their salience or intensity increases when they occur by surprise. Thus, adaptive behavior may require that neural circuits compute both stimulus valence--or value--and intensity. To explore how these computations may be implemented, we examined neural responses in the primate amygdala to unexpected reinforcement during learning. Many amygdala neurons responded differently to reinforcement depending upon whether or not it was expected. In some neurons, this modulation occurred only for rewards or aversive stimuli, but not both. In other neurons, expectation similarly modulated responses to both rewards and punishments. These different neuronal populations may subserve two sorts of processes mediated by the amygdala: those activated by surprising reinforcements of both valences-such as enhanced arousal and attention-and those that are valence-specific, such as fear or reward-seeking behavior.     

Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep

Previous work showed that sleep is associated with increased brain protein synthesis and that arrest of protein synthesis facilitates sleep. Arrest of protein synthesis is induced during the endoplasmic reticulum (ER) stress response, through phosphorylation of eukaryotic initiation factor 2alpha (p-eIF2alpha). We tested a hypothesis that elevation of p-eIF2alpha would facilitate sleep. We studied the effects of intracerebroventricular infusion of salubrinal (Salub), which increases p-eIF2alpha by inhibiting its dephosphorylation. Salub increased deep slow wave sleep by 255%, while reducing active waking by 49%. Delta power within non-rapid eye movement (NREM) sleep was increased, while power in the sigma, beta, and gamma bands during NREM was reduced. We found that Salub increased expression of p-eIF2alpha in the basal forebrain (BF) area, a sleep-wake regulatory brain region. Therefore, we quantified the p-eIF2alpha-immunolabeled neurons in the BF area; Salub administration increased the number of p-eIF2alpha-expressing noncholinergic neurons in the caudal BF. In addition, Salub also increased the intensity of p-eIF2alpha expression in both cholinergic and noncholinergic neurons, but this was more widespread among the noncholinergic neurons. Our findings support a hypothesis that sleep is facilitated by signals associated with the ER stress response.     

Dopamine in motivational control: rewarding, aversive, and alerting

Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in?positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but nonrewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and nonreward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior.     

Information processing in noisy burster models of sensory neurons

Processing of external stimuli by sensory neurons often involves bursting, when epochs of fast firing alternate with intervals of quiescence. In particular, sensory neurons of electroreceptors in paddlefish (Polyodon spathula) undergo bursting when stimulated externally with broad-band noise, but otherwise fire spontaneously in a quasiperiodic tonic manner. We use a simple phenomenological model for noise-induced bursting to quantify analytically, by means of the Kullback entropy and Fisher information, the gain in information transfer and electroreceptor sensitivity for external noisy stimuli. A good agreement between theoretical predictions, numerical simulations and experimental data is shown.     

In vitro and in vivo responses of saccular and caudal nucleus neurons in the grassfrog (Rana temporaria).

We present results from in vitro and in vivo studies of response properties of neurons in the saccular and caudal nuclei in the frog. In the in vitro studies the saccular nerve of the isolated brain was stimulated with electrical pulses. In the in vivo experiments, the neurons were stimulated by dorso-ventral vibrations of the intact animal. We identified six response types: (1) primary-like cells with short latencies and follow repetition rates up to 100 Hz; (2) phasic cells responding only to the first pulse in a train; (3) bursting cells firing several spikes in response to any stimulation; (4) late responders with very long latencies; (5) integrator cells showing facilitated responses, and (6) inhibitory cells inhibited by saccular nerve stimulation.The cells have comparable sensitivity and frequency characteristics to the primary fibres (BF 10-80 Hz, thresholds from 0.01 cm/s2) and enable a sophisticated analysis of vibrational stimuli.     

To Burst or Not to Burst?

It is well known that some neurons tend to fire packets of action potentials followed by periods of quiescence (bursts) while others within the same stage of sensory processing fire in a tonic manner. However, the respective computational advantages of bursting and tonic neurons for encoding time varying signals largely remain a mystery. Weakly electric fish use cutaneous electroreceptors to convey information about sensory stimuli and it has been shown that some electroreceptors exhibit bursting dynamics while others do not. In this study, we compare the neural coding capabilities of tonically firing and bursting electroreceptor model neurons using information theoretic measures. We find that both bursting and tonically firing model neurons efficiently transmit information about the stimulus. However, the decoding mechanisms that must be used for each differ greatly: a non-linear decoder would be required to extract all the available information transmitted by the bursting model neuron whereas a linear one might suffice for the tonically firing model neuron. Further investigations using stimulus reconstruction techniques reveal that, unlike the tonically firing model neuron, the bursting model neuron does not encode the detailed time course of the stimulus. A novel measure of feature detection reveals that the bursting neuron signals certain stimulus features. Finally, we show that feature extraction and stimulus estimation are mutually exclusive computations occurring in bursting and tonically firing model neurons, respectively. Our results therefore suggest that stimulus estimation and feature extraction might be parallel computations in certain sensory systems rather than being sequential as has been previously proposed.     

Quantifying individual variation in the propensity to attribute incentive salience to reward cues

If reward-associated cues acquire the properties of incentive stimuli they can come to powerfully control behavior, and potentially promote maladaptive behavior. Pavlovian incentive stimuli are defined as stimuli that have three fundamental properties: they are attractive, they are themselves desired, and they can spur instrumental actions. We have found, however, that there is considerable individual variation in the extent to which animals attribute Pavlovian incentive motivational properties ("incentive salience") to reward cues. The purpose of this paper was to develop criteria for identifying and classifying individuals based on their propensity to attribute incentive salience to reward cues. To do this, we conducted a meta-analysis of a large sample of rats (N = 1,878) subjected to a classic Pavlovian conditioning procedure. We then used the propensity of animals to approach a cue predictive of reward (one index of the extent to which the cue was attributed with incentive salience), to characterize two behavioral phenotypes in this population: animals that approached the cue ("sign-trackers") vs. others that approached the location of reward delivery ("goal-trackers"). This variation in Pavlovian approach behavior predicted other behavioral indices of the propensity to attribute incentive salience to reward cues. Thus, the procedures reported here should be useful for making comparisons across studies and for assessing individual variation in incentive salience attribution in small samples of the population, or even for classifying single animals.     

A Neural Computational Model of Incentive Salience

Incentive salience is a motivational property with ‘magnet-like’ qualities. When attributed to reward-predicting stimuli (cues), incentive salience triggers a pulse of ‘wanting’ and an individual is pulled toward the cues and reward. A key computational question is how incentive salience is generated during a cue re-encounter, which combines both learning and the state of limbic brain mechanisms. Learning processes, such as temporal-difference models, provide one way for stimuli to acquire cached predictive values of rewards. However, empirical data show that subsequent incentive values are also modulated on the fly by dynamic fluctuation in physiological states, altering cached values in ways requiring additional motivation mechanisms. Dynamic modulation of incentive salience for a Pavlovian conditioned stimulus (CS or cue) occurs during certain states, without necessarily requiring (re)learning about the cue. In some cases, dynamic modulation of cue value occurs during states that are quite novel, never having been experienced before, and even prior to experience of the associated unconditioned reward in the new state. Such cases can include novel drug-induced mesolimbic activation and addictive incentive-sensitization, as well as natural appetite states such as salt appetite. Dynamic enhancement specifically raises the incentive salience of an appropriate CS, without necessarily changing that of other CSs. Here we suggest a new computational model that modulates incentive salience by integrating changing physiological states with prior learning. We support the model with behavioral and neurobiological data from empirical tests that demonstrate dynamic elevations in cue-triggered motivation (involving natural salt appetite, and drug-induced intoxication and sensitization). Our data call for a dynamic model of incentive salience, such as presented here. Computational models can adequately capture fluctuations in cue-triggered ‘wanting’ only by incorporating modulation of previously learned values by natural appetite and addiction-related states.     

Distinct neuronal types contribute to hybrid temporal encoding strategies in primate auditory cortex

Studies of the encoding of sensory stimuli by the brain often consider recorded neurons as a pool of identical units. Here, we report divergence in stimulus-encoding properties between subpopulations of cortical neurons that are classified based on spike timing and waveform features. Neurons in auditory cortex of the awake marmoset (Callithrix jacchus) encode temporal information with either stimulus-synchronized or nonsynchronized responses. When we classified single-unit recordings using either a criteria-based or an unsupervised classification method into regular-spiking, fast-spiking, and bursting units, a subset of intrinsically bursting neurons formed the most highly synchronized group, with strong phase-locking to sinusoidal amplitude modulation (SAM) that extended well above 20 Hz. In contrast with other unit types, these bursting neurons fired primarily on the rising phase of SAM or the onset of unmodulated stimuli, and preferred rapid stimulus onset rates. Such differentiating behavior has been previously reported in bursting neuron models and may reflect specializations for detection of acoustic edges. These units responded to natural stimuli (vocalizations) with brief and precise spiking at particular time points that could be decoded with high temporal stringency. Regular-spiking units better reflected the shape of slow modulations and responded more selectively to vocalizations with overall firing rate increases. Population decoding using time-binned neural activity found that decoding behavior differed substantially between regular-spiking and bursting units. A relatively small pool of bursting units was sufficient to identify the stimulus with high accuracy in a manner that relied on the temporal pattern of responses. These unit type differences may contribute to parallel and complementary neural codes.

Neurons in auditory cortex show highly diverse responses to sounds. This study suggests that neuronal type inferred from baseline firing properties accounts for much of this diversity, with a subpopulation of bursting units being specialized for precise temporal encoding.     

Firing synchronization and temporal order in noisy neuronal networks

Noise-induced complete synchronization and frequency synchronization in coupled spiking and bursting neurons are studied firstly. The effects of noise and coupling are discussed. It is found that bursting neurons are easier to achieve firing synchronization than spiking ones, which means that bursting activities are more important for information transfer in neuronal networks. Secondly, the effects of noise on firing synchronization in a noisy map neuronal network are presented. Noise-induced synchronization and temporal order are investigated by means of the firing rate function and the order index. Firing synchronization and temporal order of excitatory neurons can be greatly enhanced by subthreshold stimuli with resonance frequency. Finally, it is concluded that random perturbations play an important role in firing activities and temporal order in neuronal networks.     

Stimulus-driven orienting of visuo-spatial attention in complex dynamic environments

In everyday life attention operates within complex and dynamic environments, while laboratory paradigms typically employ simple and stereotyped stimuli. This fMRI study investigated stimulus-driven spatial attention using a virtual-environment video. We explored the influence of bottom-up signals by computing saliency maps of the environment and by introducing attention-grabbing events in the video. We parameterized the efficacy of these signals for the orienting of spatial attention by measuring eye movements and used these parameters to analyze the imaging data. The efficacy of bottom-up signals modulated ongoing activity in dorsal fronto-parietal regions and transient activation of the ventral attention system. Our results demonstrate that the combination of computational, behavioral, and imaging techniques enables studying cognitive functions in ecologically valid contexts. We highlight the central role of the efficacy of stimulus-driven signals in both dorsal and ventral attention systems, with a dissociation of the efficacy of background salience versus distinctive events in the two systems.     

Spiking patterns and their functional implications in the antennal lobe of the tobacco hornworm Manduca sexta

Bursting as well as tonic firing patterns have been described in various sensory systems. In the olfactory system, spontaneous bursts have been observed in neurons distributed across several synaptic levels, from the periphery, to the olfactory bulb (OB) and to the olfactory cortex. Several in vitro studies indicate that spontaneous firing patterns may be viewed as "fingerprints" of different types of neurons that exhibit distinct functions in the OB. It is still not known, however, if and how neuronal burstiness is correlated with the coding of natural olfactory stimuli. We thus conducted an in vivo study to probe this question in the OB equivalent structure of insects, the antennal lobe (AL) of the tobacco hornworm Manduca sexta. We found that in the moth's AL, both projection (output) neurons (PNs) and local interneurons (LNs) are spontaneously active, but PNs tend to produce spike bursts while LNs fire more regularly. In addition, we found that the burstiness of PNs is correlated with the strength of their responses to odor stimulation--the more bursting the stronger their responses to odors. Moreover, the burstiness of PNs was also positively correlated with the spontaneous firing rate of these neurons, and pharmacological reduction of bursting resulted in a decrease of the neurons' responsiveness. These results suggest that neuronal burstiness reflects a physiological state of these neurons that is directly linked to their response characteristics.     

Ionic and neuromodulatory regulation of burst discharge controls frequency tuning

Sensory neurons encode natural stimuli by changes in firing rate or by generating specific firing patterns, such as bursts. Many neural computations rely on the fact that neurons can be tuned to specific stimulus frequencies. It is thus important to understand the mechanisms underlying frequency tuning. In the electrosensory system of the weakly electric fish, Apteronotus leptorhynchus, the primary processing of behaviourally relevant sensory signals occurs in pyramidal neurons of the electrosensory lateral line lobe (ELL). These cells encode low frequency prey stimuli with bursts of spikes and high frequency communication signals with single spikes. We describe here how bursting in pyramidal neurons can be regulated by intrinsic conductances in a cell subtype specific fashion across the sensory maps found within the ELL, thereby regulating their frequency tuning. Further, the neuromodulatory regulation of such conductances within individual cells and the consequences to frequency tuning are highlighted. Such alterations in the tuning of the pyramidal neurons may allow weakly electric fish to preferentially select for certain stimuli under various behaviourally relevant circumstances.     

Monoamine release by neurons of a primitive nervous system: an amperometric study

We measured monoamine release from dissociated neurons of the sea pansy Renilla koellikeri, a representative of the most evolutionarily ancient animals with nervous systems, by real-time monitoring of exocytosis using the amperometric method with carbon-fiber microelectrodes. Depolarization-induced, as well as spontaneously active, neurons exhibited calcium-dependent exocytotic events at both the soma and the terminal bulb of neuritic processes. All spontaneously active neurons exhibited a bursting activity pattern in which amplitudes of exocytotic events appeared to be distributed in a quantal-like fashion. Fast Fourier transform analysis of bursting activity in 20 such neurons revealed burst harmonics with a major frequency of 8 Hz and a dominant rate of 95 Hz for individual exocytotic events within bursts. The results suggest that exocytotic transmitter release is as ancient as neurons and that endogenously bursting neurons in the sea pansy are as complex as those of higher animals. In addition, the observation that both soma and neuritic terminals of the same neuron can release transmitter suggests that local release sites in these cnidarian neurons are not critical for nerve net function.     

Central representation of internal and external sensory information in the CNS of Helix pomatia L. and Lymnaea stagnalis L

The central representation of intero- and exteroreceptors located in visceral organs and the osphradium were compared in the CNS of Helix pomatia L. (Gastropoda, Stylommatophora) and Lymnaea stagnalis L. (Gastropoda, Basommatophora), two pulmonate snail species inhabiting a terrestrial and anaquatic environment, respectively. Semi-intact preparations were used comprising the CNS connected by the corresponding nerves either to the cardio-renal, respiratory and genital systems or to the osphradium. Spike discharges of central neurons and the nerves were recorded simultaneously. The central representation of intero- and exteroreceptors was found to be distributed throughout the CNS and involved about 300 neurons. The majority of the neurons received sensory information from all the studied visceral organs and the osphradium. Among the neurons responding to intero- and exteroreceptors a multimodal reaction to tactile, chemical and osmotic stimuli prevailed while in the osphradium specific reactions also were demonstrated. Central neurons receiving sensory information from visceral organs and the osphradium form overlapping and reorganizing neural circuits using the same neurons in the regulation of heart activity, respiration or reproduction producing the appropriate behaviour. In the selection of sensory information the firing pattern appears to be the main determining factor as bursting neurons do not receive sensory information. The central representation of intero- and exteroreceptors and its variability can be a model system for cellular studies of motivational state and self-perception.     

Spatial attention and neglect: parietal, frontal and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events.

The syndrome of contralesional neglect reflects a lateralized disruption of spatial attention. In the human, the left hemisphere shifts attention predominantly in the contralateral hemispace and in a contraversive direction whereas the right hemisphere distributes attention more evenly, in both hemispaces and both directions. As a consequence of this asymmetry, severe contralesional neglect occurs almost exclusively after right hemisphere lesions. Patients with left neglect experience a loss of salience in the mental representation and conscious perception of the left side and display a reluctance to direct orientating and exploratory behaviours to the left. Neglect is distributed according to egocentric, allocentric, world-centred, and object-centred frames of reference. Neglected events can continue to exert an implicit influence on behaviour, indicating that the attentional filtering occurs at the level of an internalized representation rather than at the level of peripheral sensory input. The unilateral neglect syndrome is caused by a dysfunction of a large-scale neurocognitive network, the cortical epicentres of which are located in posterior parietal cortex, the frontal eye fields, and the cingulate gyrus. This network coordinates all aspects of spatial attention, regardless of the modality of input or output. It helps to compile a mental representation of extrapersonal events in terms of their motivational salience, and to generate 'kinetic strategies' so that the attentional focus can shift from one target to another.     

Reconciling the influence of predictiveness and uncertainty on stimulus salience: a model of attention in associative learning

Theories of selective attention in associative learning posit that the salience of a cue will be high if the cue is the best available predictor of reinforcement (high predictiveness). In contrast, a different class of attentional theory stipulates that the salience of a cue will be high if the cue is an inaccurate predictor of reinforcement (high uncertainty). Evidence in support of these seemingly contradictory propositions has led to: (i) the development of hybrid attentional models that assume the coexistence of separate, predictiveness-driven and uncertainty-driven mechanisms of changes in cue salience; and (ii) a surge of interest in identifying the neural circuits underpinning these mechanisms. Here, we put forward a formal attentional model of learning that reconciles the roles of predictiveness and uncertainty in salience modification. The issues discussed are relevant to psychologists, behavioural neuroscientists and neuroeconomists investigating the roles of predictiveness and uncertainty in behaviour.