The role of somatosensation in automatic visuo-motor control: a comparison of congenital and acquired sensory loss.

Studies of chronically deafferented participants have illuminated how regaining some motor control after adult-onset loss of proprioceptive and touch input depends heavily on cognitive control. In this study we contrasted the performance of one such man, IW, with KS, a woman born without any somatosensory fibres. We postulated that her life-long absence of proprioception and touch might have allowed her to automate some simple visually-guided actions, something IW appears unable to achieve. We tested these two, and two age-matched control groups, on writing and drawing tasks performed with and without an audio-verbal echoing task that added a cognitive demand. In common with other studies of skilled action, the dual task was shown to affect visuo-motor performance in controls, with less well-controlled drawing and writing, evident as increases in path speed and reduction in curvature and trial duration. We found little evidence that IW was able to automate even the simplest drawing tasks and no evidence for automaticity in his writing. In contrast, KS showed a selective increase in speed of signature writing under the dual-task conditions, suggesting some ability to automate her most familiar writing. We also tested tracing of templates under mirror-reversed conditions, a task that imposes a powerful cognitive planning challenge. Both IW and KS showed evidence of a visuo-motor planning conflict, as did the controls, for shapes with sharp corners. Overall, IW was much faster than his controls to complete tracing shapes, consistent with an absence of visuo-proprioceptive conflict, whereas KS was slower than her controls, especially as the corners became sharper. She dramatically improved after a short period of practice while IW did not. We conclude that KS, who developed from birth without proprioception, may have some visually derived control of movement not under cognitive control, something not seen in IW. This allowed her to automate some writing and drawing actions, but impaired her initial attempts at mirror-tracing. In contrast, IW, who lost somatosensation as an adult, cannot automate these visually guided actions.

Perception of body shape and size without touch or proprioception: evidence from individuals with congenital and acquired neuropathy.

The degree to which mental representations of the body can be established and maintained without somatosensory input remains unclear. We contrast two "deafferented" adults, one who acquired large fibre sensory loss as an adult (IW) and another who was born without somatosensation (KS). We compared their responses to those of matched controls in three perceptual tasks: first accuracy of their mental image of their hands (assessed by testing recognition of correct hand length/width ratio in distorted photographs and by locating landmarks on the unseen hand); then accuracy of arm length judgements (assessed by judgement of reaching distance), and finally, we tested for an attentional bias towards peri-personal space (assessed by reaction times to visual target presentation). We hypothesised that IW would demonstrate responses consistent with him accessing conscious knowledge, whereas KS might show evidence of responses dependent on non-conscious mechanisms. In the first two experiments, both participants were able to give consistent responses about hand shape and arm length, but IW displayed a better awareness of hand shape than KS (and controls). KS demonstrated poorer spatial accuracy in reporting hand landmarks than both IW and controls, and appears to have less awareness of her hands. Reach distance was overestimated by both IW and KS, as it was for controls; the precision of their judgements was slightly lower than that of the controls. In the attentional task, IW showed no reaction time differences across conditions in the visual detection task, unlike controls, suggesting that he has no peri-personal bias of attention. In contrast, KS did show target location-dependent modulation of reaction times, when her hands were visible. We suggest that both IW and KS can access a conscious body image, although its accuracy may reflect their different experience of hand action. Acquired sensory loss has deprived IW of any subconscious body awareness, but the congenital absence of somatosensation may have led to its partial replacement by a form of visual proprioception in KS.

Lessons from helping behavior in rats.

Helping involves other-oriented actions that have the potential to benefit another. The last ten years has seen the introduction of several experimental paradigms to study helping in rats. In the best characterized of these, a free rat opens a door to release a rat trapped in an acrylic tube or pool of water. Helping is proffered independent of the opportunity to socially interact. Both an absence and an excess of affective arousal or anxiety antagonize helping whereas mild levels of distress facilitate helping. Helping is socially selective and highly sensitive to the social environment with non-helpers antagonizing and additional helpers facilitating another rat's propensity to help.

Behavioral Tests for Mouse Models of Autism: An Argument for the Inclusion of Cerebellum-Controlled Motor Behaviors.

Mouse models of Autism Spectrum Disorder (ASD) have been interrogated using a variety of behavioral tests in order to understand the symptoms of ASD. However, the hallmark behaviors that are classically affected in ASD - deficits in social interaction and communication as well as the occurrence of repetitive behaviors - do not have direct murine equivalents. Thus, it is critical to identify the caveats that come with modeling a human disorder in mice. The most commonly used behavioral tests represent complex cognitive processes based on largely unknown brain circuitry. Motor impairments provide an alternative, scientifically rigorous approach to understanding ASD symptoms. Difficulties with motor coordination and learning - seen in both patients and mice - point to an involvement of the cerebellum in ASD pathology. This brain area supports types of motor learning that are conserved throughout vertebrate evolution, allowing for direct comparisons of functional abnormalities between humans with autism and ASD mouse models. Studying simple motor behaviors provides researchers with clearly interpretable results. We describe and evaluate methods used on mouse behavioral assays designed to test for social, communicative, perseverative, anxious, nociceptive, and motor learning abnormalities. We comment on the effectiveness and validity of each test based on how much information its results give, as well as its relevance to ASD, and will argue for an inclusion of cerebellum-supported motor behaviors in the phenotypic description of ASD mouse models. LAY SUMMARY: Mouse models of Autism Spectrum Disorder help us gain insight about ASD symptoms in human patients. However, there are many differences between mice and humans, which makes interpreting behaviors challenging. Here, we discuss a battery of behavioral tests for specific mouse behaviors to explore whether each test does indeed evaluate the intended measure, and whether these tests are useful in learning about ASD.

The bystander effect in rats.

To investigate whether the classic bystander effect is unique to humans, the effect of bystanders on rat helping was studied. In the presence of rats rendered incompetent to help through pharmacological treatment, rats were less likely to help due to a reduction in reinforcement rather than to a lack of initial interest. Only incompetent helpers of a strain familiar to the helper rat exerted a detrimental effect on helping; rats helped at near control levels in the presence of incompetent helpers from an unfamiliar strain. Duos and trios of potential helper rats helped at superadditive rates, demonstrating that rats act nonindependently with helping facilitated by the presence of competent-to-help bystanders. Furthermore, helping was facilitated in rats that had previously observed other rats' helping and were then tested individually. In sum, the influence of bystanders on helping behavior in rats features characteristics that closely resemble those observed in humans.

A valence-free definition of sociality as any violation of inter-individual independence.

Well over 90% of studies in biomedical sciences are performed on single animals. While knowledge of the genetics, development and physiology of single individuals accrues, an understanding of the biological mechanisms by which individuals interact has barely budged. Yet many of society's greatest problems derive from an inability of humans to get along with each other. Studies in social neuroscience are primarily observational and rarely employ subjects who physically interact. Thus, social interaction represents a largely unexplored frontier of biology. The neuroscience that underlies social behaviour and interactions can and should be studied using the scientific method. However, a workable and objective definitional framework of sociality is needed for scientific progress in this field. Here we propose a definition that uses a test of independence from the presence of others. The null hypothesis is that a behaviour is independent from the influence of others. Rejection of this null hypothesis means that the actions of an individual depend on the actions of one or more other individuals. This definition has the advantages of not being contaminated by moral judgements or biases in favour of pro-social behaviour, and of being applicable to a wide range of physiological processes. The definition of a social behaviour proposed here says nothing regarding the valence of the behaviour with respect to others. Thus, a behaviour that is influenced by the presence of others may benefit, harm, or have no effect on others. It is hoped that this definitional framework for sociality will facilitate our understanding of the origins and mechanisms of social behaviour among animals including humans as well as offer efficacious approaches to social disorders such as autism.

Nicotinic modulation of descending pain control circuitry.

Along with the well-known rewarding effects, activation of nicotinic acetylcholine receptors (nAChRs) can also relieve pain, and some nicotinic agonists have analgesic efficacy similar to opioids. A major target of analgesic drugs is the descending pain modulatory pathway, including the ventrolateral periaqueductal gray (vlPAG) and the rostral ventromedial medulla (RVM). Although activating nAChRs within this circuitry can be analgesic, little is known about the subunit composition and cellular effects of these receptors, particularly within the vlPAG. Using electrophysiology in brain slices from adult male rats, we examined nAChR effects on vlPAG neurons that project to the RVM. We found that 63% of PAG-RVM projection neurons expressed functional nAChRs, which were exclusively of the α7-subtype. Interestingly, the neurons that express α7 nAChRs were largely nonoverlapping with those expressing µ-opioid receptors (MOR). As nAChRs are excitatory and MORs are inhibitory, these data suggest distinct roles for these neuronal classes in pain modulation. Along with direct excitation, we also found that presynaptic nAChRs enhanced GABAergic release preferentially onto neurons that lacked α7 nAChRs. In addition, presynaptic nAChRs enhanced glutamatergic inputs onto all PAG-RVM projection neuron classes to a similar extent. In behavioral testing, both systemic and intra-vlPAG administration of the α7 nAChR-selective agonist, PHA-543,613, was antinociceptive in the formalin assay. Furthermore, intra-vlPAG α7 antagonist pretreatment blocked PHA-543,613-induced antinociception via either administration method. Systemic administration of submaximal doses of the α7 agonist and morphine produced additive antinociceptive effects. Together, our findings indicate that the vlPAG is a key site of action for α7 nAChR-mediated antinociception.

Anxiolytic Treatment Impairs Helping Behavior in Rats.

Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats' subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat's behavior on one session influenced his behavior on the next session. Results suggest that helping a trapped rat has a greater motivational value than does chocolate. In sum, this series of experiments clearly demonstrates the fundamental role of affect in motivating pro-social behavior in rodents and the need for a helper to resonate with the affect of a victim.

Pro-social behavior in rats is modulated by social experience.

In mammals, helping is preferentially provided to members of one's own group. Yet, it remains unclear how social experience shapes pro-social motivation. We found that rats helped trapped strangers by releasing them from a restrainer, just as they did cagemates. However, rats did not help strangers of a different strain, unless previously housed with the trapped rat. Moreover, pair-housing with one rat of a different strain prompted rats to help strangers of that strain, evidence that rats expand pro-social motivation from one individual to phenotypically similar others. To test if genetic relatedness alone can motivate helping, rats were fostered from birth with another strain and were not exposed to their own strain. As adults, fostered rats helped strangers of the fostering strain but not rats of their own strain. Thus, strain familiarity, even to one's own strain, is required for the expression of pro-social behavior. DOI: http://dx.doi.org/10.7554/eLife.01385.001.

Caffeine accelerates recovery from general anesthesia.

General anesthetics inhibit neurotransmitter release from both neurons and secretory cells. If inhibition of neurotransmitter release is part of an anesthetic mechanism of action, then drugs that facilitate neurotransmitter release may aid in reversing general anesthesia. Drugs that elevate intracellular cAMP levels are known to facilitate neurotransmitter release. Three cAMP elevating drugs (forskolin, theophylline, and caffeine) were tested; all three drugs reversed the inhibition of neurotransmitter release produced by isoflurane in PC12 cells in vitro. The drugs were tested in isoflurane-anesthetized rats. Animals were injected with either saline or saline containing drug. All three drugs dramatically accelerated recovery from isoflurane anesthesia, but caffeine was most effective. None of the drugs, at the concentrations tested, had significant effects on breathing rates, O2 saturation, heart rate, or blood pressure in anesthetized animals. Caffeine alone was tested on propofol-anesthetized rats where it dramatically accelerated recovery from anesthesia. The ability of caffeine to accelerate recovery from anesthesia for different chemical classes of anesthetics, isoflurane and propofol, opens the possibility that it will do so for all commonly used general anesthetics, although additional studies will be required to determine whether this is in fact the case. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in human patients.

Opioids disrupt pro-nociceptive modulation mediated by raphe magnus.

In anesthetized rats, opioid analgesia is accompanied by a specific pattern of tonic activity in two neuronal populations within the medullary raphe magnus (RM): opioids silence pain-facilitatory ON cells and produce sustained discharge in pain-inhibitory OFF cells. These tonic activity patterns, hypothesized to generate a tonic analgesic state, have not been observed in recordings made without anesthesia. Therefore, we recorded ON and OFF cell activity before and after an analgesic dose of morphine in unanesthetized mice. The tonic activity of ON and OFF cells was unchanged by morphine. Rather, morphine suppressed the phasic ON cell excitation and OFF cell inhibition evoked by noxious stimulation. Before morphine, the magnitude of the noxious stimulus-evoked burst in ON cells correlated with motor withdrawal magnitude, suggesting that ON cells facilitate nocifensive motor reactions. Contrary to model prediction, OFF cell activity was greater before stimulus trials that evoked withdrawals than those without withdrawals. Since withdrawals only occurred when OFF cell activity was suppressed, a decrease in OFF cell activity appears to serve as a pro-nociceptive signal that synchronizes and therefore strengthens the ensuing motor reaction. We further propose that morphine acts in RM to suppress ON and OFF cell phasic responses and thereby disable RM's pro-nociceptive output. Thus, RM cells produce antinociception by failing to exert the pro-nociceptive effects normally engaged by noxious stimulation. These findings revise the conventional understanding of supraspinal opioid analgesia and demonstrate that RM produces on demand rather than state modulation, allowing RM cells to serve other functions during pain-free periods.

Medullary circuits for nociceptive modulation.

Neurons in the medullary raphe are critical to opioid analgesia through descending projections to the dorsal horn. Work in anesthetized rats led to the postulate that nociceptive suppression results from tonic activation of nociceptive-inhibiting neurons and tonic inhibition of nociceptive-facilitating neurons. However, morphine does not cause tonic changes in raphe neuronal firing in unanesthetized rodents. Recent work suggests that a drop in activity of nociceptive-inhibiting neurons synchronizes nociceptive circuits and a burst of activity in nociceptive-facilitating neurons facilitates withdrawal magnitude. After morphine, the phasic responses of raphe cells are suppressed along with nociceptive withdrawals. The results suggest a new model of brainstem modulation of nociception in which the medullary raphe facilitates nociceptive reactions when noxious input occurs and may modulate other functions between injurious events.

Empathy and pro-social behavior in rats.

Whereas human pro-social behavior is often driven by empathic concern for another, it is unclear whether nonprimate mammals experience a similar motivational state. To test for empathically motivated pro-social behavior in rodents, we placed a free rat in an arena with a cagemate trapped in a restrainer. After several sessions, the free rat learned to intentionally and quickly open the restrainer and free the cagemate. Rats did not open empty or object-containing restrainers. They freed cagemates even when social contact was prevented. When liberating a cagemate was pitted against chocolate contained within a second restrainer, rats opened both restrainers and typically shared the chocolate. Thus, rats behave pro-socially in response to a conspecific's distress, providing strong evidence for biological roots of empathically motivated helping behavior.

Ingestion analgesia occurs when a bad taste turns good.

During ingestion of water, chocolate, sucrose, and saccharin, pain-related behaviors are suppressed. This ingestion analgesic effect is reversed when the hedonic valence of a food is switched from "good" to "bad" as occurs during conditioned taste aversion. Here, we tested the converse hedonic shift to determine if ingestion analgesia occurs when 0.3 M NaCl is made palatable by inducing a sodium appetite. In Experiment 1, sham- and sodium-depleted rats were tested for paw withdrawal and lick latencies to brief noxious heat during quiet wake and intraoral NaCl ingestion. Only sodium-depleted rats showed a suppression of heat-evoked reactions during NaCl ingestion. In Experiment 2, we tested whether this analgesic effect is mediated by the brainstem nucleus raphe magnus (NRM). Inactivation of NRM with muscimol blocked ingestion analgesia during NaCl ingestion by sodium-depleted rats. This attenuation was not due to a hyperalgesic effect of NRM inactivation. Muscimol microinjections into a nearby region, the nucleus raphe obscurus (NRO), were ineffective. The present findings demonstrate that the internal milieu of an animal can modify ingestion analgesia, and that the analgesia during NaCl ingestion by sodium hungry rats is mediated by NRM.

The modulatory effects of rostral ventromedial medulla on air-puff evoked microarousals in rats.

This study tested whether the duration of microarousals from sleep evoked by innocuous air-puff is affected by intra-RVM administration of neurotensin and bicuculline, pharmacological manipulations that affect on and off cell activity. Air-puff evoked microarousal duration was unaffected by 0.05ng neurotensin, but decreased by 502ng neurotensin, and 5 and 50ng bicuculline. These results suggest a putative role for off cells in protecting sleep from interruption by non-noxious stimuli.

How the social brain experiences empathy: Summary of a gathering.

Explaining how, and even why, the social brain experiences empathy is a complex integrative endeavor that has been explored by scientists of several disciplines working with both animal and human subjects. Current thoughts on empathy and its connection to behavior­prosocial, altruistic, and cruel alike­were explored by scholars in the fields of biology, philosophy, psychology, and anthropology at a conference in Chicago. The speakers' individually unique perspectives merged to provide an inclusive overview of the biological basis of, and cultural influences upon, empathy. The nature of empathy in nonhuman animals, the endocrine requirements for empathy,the effects of empathy on moral behavior, the social nature of pain, the relation between empathy and altruism,the ethnography of empathy, and empathy in the medical setting were discussed. The interdisciplinary nature of the conference demonstrated the advantages of communicating findings across fields while also delineating the difficulties that can stem from the existence of multiple approaches to, and definitions of, empathy. Future progress will be aided by working toward common definitions for empathy, sympathy, altruism, and so on, in concert with cross-disciplinary dialogues that allow practitioners of each discipline to be informed by paradigms and findings from complementary disciplines.