Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex.

All animals possess a repertoire of innate (or instinctive) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents. We used microendoscopy to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a 'hard-wired' system.

Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus.

Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases that are associated with increasing levels of arousal. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male-male and male-female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1(+) (but not Esr1(-)) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1(+) neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1(+) neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.

Monkey drumming reveals common networks for perceiving vocal and nonvocal communication sounds.

Salient sounds such as those created by drumming can serve as means of nonvocal acoustic communication in addition to vocal sounds. Despite the ubiquity of drumming across human cultures, its origins and the brain regions specialized in processing such signals remain unexplored. Here, we report that an important animal model for vocal communication, the macaque monkey, also displays drumming behavior, and we exploit this finding to show that vocal and nonvocal communication sounds are represented by overlapping networks in the brain's temporal lobe. Observing social macaque groups, we found that these animals use artificial objects to produce salient periodic sounds, similar to acoustic gestures. Behavioral tests confirmed that these drumming sounds attract the attention of listening monkeys similarly as conspecific vocalizations. Furthermore, in a preferential looking experiment, drumming sounds influenced the way monkeys viewed their conspecifics, suggesting that drumming serves as a multimodal signal of social dominance. Finally, by using high-resolution functional imaging we identified those brain regions preferentially activated by drumming sounds or by vocalizations and found that the representations of both these communication sounds overlap in caudal auditory cortex and the amygdala. The similar behavioral responses to drumming and vocal sounds, and their shared neural representation, suggest a common origin of primate vocal and nonvocal communication systems and support the notion of a gestural origin of speech and music.

Unimodal responses prevail within the multisensory claustrum.

The claustrum receives afferent inputs from multiple sensory-related brain areas, prompting speculation about a role in integrating information across sensory modalities. Here we directly test this hypothesis by probing neurons in the primate claustrum for functional characteristics of multisensory processing. To this end we recorded neuronal responses to naturalistic audio-visual stimuli from the claustra of alert monkeys. Our results reveal the existence of distinct claustral zones comprised of unimodal neurons associated with the auditory and visual modalities. In a visual zone within the ventral claustrum neurons responded to visual stimuli but not to sounds, whereas in an auditory zone located within the central claustrum neurons responded to sounds but not to visual stimuli. Importantly, we find that neurons within either zone are not influenced by stimuli in the other modality and do not exhibit the typical response characteristics usually associated with multisensory processing. While these results confirm the notion of the claustrum as a multisensory structure per se, they argue against the hypothesis of the claustrum serving as an integrator of sensory information.

Signals from the edges: the cortical hem and antihem in telencephalic development.

The early cortical primordium develops from a sheet of neuroepithelium that is flanked by distinct signaling centers. Of these, the hem and the antihem are positioned as longitudinal stripes, running rostro-caudally along the medial and lateral faces, respectively, of each telencepahlic hemisphere. In this review we examine the similarities and differences in how these two signaling centers arise, their roles in patterning adjacent tissues, and the cells and structures they contribute to. Since both the hem and the antihem have been identified across many vertebrate phyla, they appear to be part of an evolutionary conserved set of mechanisms that play fundamental roles in forebrain development.

A stream of cells migrating from the caudal telencephalon reveals a link between the amygdala and neocortex.

The amygdaloid complex consists of diverse nuclei that belong to distinct functional systems, yet many issues about its development are poorly understood. Here, we identify a stream of migrating cells that form specific amygdaloid nuclei in mice. In utero electroporation showed that this caudal amygdaloid stream (CAS) originated in a unique domain at the caudal telencephalic pole that is contiguous with the dorsal pallium, which was previously thought to generate only neocortical cells. The CAS and the neocortex share mechanisms for specification (transcription factors Tbr1, Lhx2 and Emx1/2) and migration (reelin and Cdk5). Reelin, a critical cue for migration in the neocortex, and Cdk5, which is specifically required for migration along radial glia in the neocortex, were both selectively required for the normal migration of the CAS, but not for that of other amygdaloid nuclei. This is first evidence of a dorsal pallial contribution to the amygdala, demonstrating a developmental and mechanistic link between the amygdala and the neocortex.

An auditory region in the primate insular cortex responding preferentially to vocal communication sounds.

Human imaging studies implicate the insular cortex in processing complex sounds and vocal communication signals such as speech. In addition, lesions of the insula often manifest as deficits in sound or speech recognition (auditory agnosia) and speech production. While models of acoustic perception assign an important role to the insula, little is known about the underlying neuronal substrate. Studying a vocal primate, we identified a predominantly auditory region in the caudal insula and therein discovered a neural representation of conspecific communication sounds. When probed with natural sounds, insula neurons exhibited higher response selectivity than neurons in auditory cortex, and in contrast to these, responded preferentially to conspecific vocalizations. Importantly, insula neurons not only preferred conspecific vocalizations over a wide range of environmental sounds and other animal vocalizations, but also over acoustically manipulated versions of these, demonstrating that this preference for vocalizations arises both from spectral and temporal features of the sounds. In addition, individual insula neurons responded highly selectively to only a few vocalizations and allowed the decoding of sound identity from single-trial responses. These findings characterize the caudal insula as a selectively responding auditory region, possibly part of a processing stream involved in the representation of communication sounds. Importantly, our results provide a neural counterpart for the human imaging and lesion findings and uncover a basis for a supposed role of the insula in processing vocal communication sounds such as speech.

Selective requirement of Pax6, but not Emx2, in the specification and development of several nuclei of the amygdaloid complex.

The amygdaloid complex is a group of nuclei that are thought to originate from multiple sites of the dorsal and ventral telencephalic neuroepithelium. The mechanisms that regulate their development are essentially unknown. We studied the role of Pax6 and Emx2, two transcription factors that regulate regional specification and growth of the telencephalon, in the morphogenesis of the amygdaloid complex. We used a set of specific marker genes that identify distinct amygdaloid nuclei to analyze Pax6/Small eye and Emx2 knock-out mutant mouse brains. We found that there is a selective requirement for Pax6, but not Emx2, in the formation a subset of nuclei within the amygdaloid complex. Specifically, structures that were not previously considered to be developmentally linked, the nucleus of the lateral olfactory tract and the lateral, basolateral, and basomedial nuclei, all appear to have a common requirement for Pax6. Together, our findings provide new insights into the origins and mechanisms underlying the development of the amygdaloid complex.

LIM genes parcellate the embryonic amygdala and regulate its development.

The mechanisms that regulate the development of the amygdaloid complex are as yet poorly understood. Here, we show that in the absence of the LIM-homeodomain (LIM-HD) gene Lhx2, a particular amygdaloid nucleus, the nucleus of the lateral olfactory tract (nLOT), is selectively disrupted. LIM family members are well suited for multiple roles in the development of complex structures because they participate in regulatory interactions that permit a diversity of function. To investigate the possible role for other LIM-HD genes as well as LIM-only (Lmo) genes in the developing amygdala, we examined their expression in the embryo. We show that amygdaloid nuclei upregulate distinct patterns of LIM gene expression from embryonic stages. This supports the hypothesis that LIM genes may participate in the mechanisms that control the development of the amygdala. The disruption of the nLOT in the Lhx2 mutant is the first evidence of a role for LIM-HD genes in the development of the amygdaloid complex. The combinatorial expression patterns of LIM genes suggest a comprehensive mechanism for patterning this structure.

Ventromedial hypothalamic neurons control a defensive emotion state.

Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

A role of the claustrum in auditory scene analysis by reflecting sensory change.

The biological function of the claustrum remains speculative, despite many years of research. On the basis of its widespread connections it is often hypothesized that the claustrum may have an integrative function mainly reflecting objects rather than the details of sensory stimuli. Given the absence of a clear demonstration of any sensory integration in claustral neurons, however, we propose an alternative, data-driven, hypothesis: namely that the claustrum detects the occurrence of novel or salient sensory events. The detection of new events is critical for behavior and survival, as suddenly appearing objects may require rapid and coordinated reactions. Sounds are of particular relevance in this regard, and our conclusions are based on the analysis of neurons in the auditory zone of the primate claustrum. Specifically, we studied the responses to natural sounds, their preference to various sound categories, and to changes in the auditory scene. In a test for sound-category preference claustral neurons responded to but displayed a clear lack of selectivity between monkey vocalizations, other animal vocalizations or environmental sounds (Esnd). Claustral neurons were however able to detect target sounds embedded in a noisy background and their responses scaled with target signal to noise ratio (SNR). The single trial responses of individual neurons suggest that these neurons detected and reflected the occurrence of a change in the auditory scene. Given its widespread connectivity with sensory, motor and limbic structures the claustrum could play the essential role of identifying the occurrence of important sensory changes and notifying other brain areas-hence contributing to sensory awareness.

Internal States and Behavioral Decision-Making: Toward an Integration of Emotion and Cognition.

Social interactions, such as an aggressive encounter between two conspecific males or a mating encounter between a male and a female, typically progress from an initial appetitive or motivational phase, to a final consummatory phase. This progression involves both changes in the intensity of the animals' internal state of arousal or motivation and sequential changes in their behavior. How are these internal states, and their escalating intensity, encoded in the brain? Does this escalation drive the progression from the appetitive/motivational to the consummatory phase of a social interaction and, if so, how are appropriate behaviors chosen during this progression? Recent work on social behaviors in flies and mice suggests possible ways in which changes in internal state intensity during a social encounter may be encoded and coupled to appropriate behavioral decisions at appropriate phases of the interaction. These studies may have relevance to understanding how emotion states influence cognitive behavioral decisions at higher levels of brain function.

Suppressive competition: how sounds may cheat sight.

In this issue of Neuron, Iurilli et al. (2012) demonstrate that auditory cortex activation directly engages local GABAergic circuits in V1 to induce sound-driven hyperpolarizations in layer 2/3 and layer 6 pyramidal neurons. Thereby, sounds can directly suppress V1 activity and visual driven behavior.

Development of midline cell types and commissural axon tracts requires Fgfr1 in the cerebrum.

The adult cerebral hemispheres are connected to each other by specialized midline cell types and by three axonal tracts: the corpus callosum, the hippocampal commissure, and the anterior commissure. Many steps are required for these tracts to form, including early patterning and later axon pathfinding steps. Here, the requirement for FGF signaling in forming midline cell types and commissural axon tracts of the cerebral hemispheres is examined. Fgfr1, but not Fgfr3, is found to be essential for establishing all three commissural tracts. In an Fgfr1 mutant, commissural neurons are present and initially project their axons, but these fail to cross the midline that separates the hemispheres. Moreover, midline patterning defects are observed in the mutant. These defects include the loss of the septum and three specialized glial cell types, the indusium griseum glia, midline zipper glia, and glial wedge. Our findings demonstrate that FGF signaling is required for generating telencephalic midline structures, in particular septal and glial cell types and all three cerebral commissures. In addition, analysis of the Fgfr1 heterozygous mutant, in which midline patterning is normal but commissural defects still occur, suggests that at least two distinct FGF-dependent mechanisms underlie the formation of the cerebral commissures.

Expression of FGF receptors 1, 2, 3 in the embryonic and postnatal mouse brain compared with Pdgfralpha, Olig2 and Plp/dm20: implications for oligodendrocyte development.

Fibroblast growth factors (FGF) receptors FgfR1, FgfR2 and FgfR3 are differentially regulated during oligodendrocyte (OL) maturation in vitro: FgfR3 is expressed by OL progenitors whereas FgfR2 is expressed by differentiated OLs [Mol Cell Neurosci 1996;7:263-275], and we have recently shown that FgfR3 is required for the timely differentiation of OLs in vivo [J Neurosci 2003;23:883-894]. Here we have used in situ hybridization to investigate the expression patterns of FgfR1-3 and compare them to the putative OL progenitor markers Olig2, Pdgfralpha and Plp/dm20 as a function of development in vivo, in particular at sites of OL specification, migration or differentiation in the mouse forebrain and cerebellum. We show that at early stages FgfR1-3 expression overlaps with that of Olig2 in the embryonic ventricular zone of the lateral and medial ganglionic eminences. Further, a scattered population of cells expressing FgfR3 (but not FgfR1 or FgfR2) in the ventral telencephalon appear to arise from the ventricular zone, and at later stages are found more dorsally in the cortex, in an overall pattern similar to Olig2 and/or Pdgfralpha. Postnatal expression of FgfR2 increases with age, more prominently in specific regions, including the cortical and cerebellar white matter and optic nerve. Thus, the differential expression pattern of FgfR2 and FgfR3 observed in vivo suggests that their expression is developmentally regulated in a manner consistent with the pattern of their expression in culture. These data provide further insights into role of FgfRs in OL development, and they emphasize that these receptors are positioned both spatially and temporally to impact OL generation in vivo.