Social Experience Interacts with Serotonin to Affect Functional Connectivity in the Social Behavior Network following Playback of Social Vocalizations in Mice.

Past social experience affects the circuitry responsible for producing and interpreting current behaviors. The social behavior network (SBN) is a candidate neural ensemble to investigate the consequences of early-life social isolation. The SBN interprets and produces social behaviors, such as vocalizations, through coordinated patterns of activity (functional connectivity) between its multiple nuclei. However, the SBN is relatively unexplored with respect to murine vocal processing. The serotonergic system is sensitive to past experience and innervates many nodes of the SBN; therefore, we tested whether serotonin signaling interacts with social experience to affect patterns of immediate early gene (IEG; cFos) induction in the male SBN following playback of social vocalizations. Male mice were separated into either social housing of three mice per cage or into isolated housing at 18-24 d postnatal. After 28-30 d in housing treatment, mice were parsed into one of three drug treatment groups: control, fenfluramine (FEN; increases available serotonin), or pCPA (depletes available serotonin) and exposed to a 60-min playback of female broadband vocalizations (BBVs). FEN generally increased the number of cFos-immunoreactive (-ir) neurons within the SBN, but effects were more pronounced in socially isolated mice. Despite a generalized increase in cFos immunoreactivity, isolated mice had reduced functional connectivity, clustering, and modularity compared with socially reared mice. These results are analogous to observations of functional dysconnectivity in persons with psychopathologies and suggests that early-life social isolation modulates serotonergic regulation of social networks.

Serotonergic innervation of the auditory midbrain: dorsal raphe subregions differentially project to the auditory midbrain in male and female mice.

In the auditory inferior colliculus (IC), serotonin reflects features of context including the valence of social interactions, stressful events, and prior social experience. However, within the dorsal raphe nucleus (DRN; B6 + B7), the source of serotonergic projections to the IC has not been resolved at the level of DRN subregions. Additionally, few studies have investigated which DRN subregions are engaged during naturalistic, sensory-driven social behaviors. We employ traditional, retrograde tract-tracing approaches to comprehensively map the topographic extent of DRN-IC projection neurons in male and female mice. We combine this approach with immediate early gene (cFos) mapping in order to describe the functional properties of DRN subregions during contexts in which serotonin fluctuates within the IC. These approaches provide novel evidence that the dorsal (DRd) and lateral (DRl) B7 subregions are primarily responsible for serotonergic innervation of the IC; further, we show that this projection is larger in male than in female mice. Additionally, DRd and the ventral B7 (DRv) contained more transcriptionally active serotonergic neurons irrespective of behavioral context. Male mice had more active serotonergic neurons in DRd and DRv than females following sociosexual encounters. However, serotonergic activity was correlated with the expression of female but not male social behaviors. The topographic organization of the DRN-IC projection provides the anatomical framework to test a mechanism underlying context-dependent auditory processing. We further highlight the importance of including sex as a biological variable when describing the functional topography of DRN.

Seasonal patterns of melatonin alter aggressive phenotypes of female Siberian hamsters.

Many animal species exhibit year-round aggression, a behaviour that allows individuals to compete for limited resources in their environment (eg, food and mates). Interestingly, this high degree of territoriality persists during the non-breeding season, despite low levels of circulating gonadal steroids (ie, testosterone [T] and oestradiol [E2 ]). Our previous work suggests that the pineal hormone melatonin mediates a 'seasonal switch' from gonadal to adrenal regulation of aggression in Siberian hamsters (Phodopus sungorus); solitary, seasonally breeding mammals that display increased aggression during the short, 'winter-like' days (SDs) of the non-breeding season. To test the hypothesis that melatonin elevates non-breeding aggression by increasing circulating and neural steroid metabolism, we housed female hamsters in long days (LDs) or SDs, administered them timed or mis-timed melatonin injections (mimic or do not mimic a SD-like signal, respectively), and measured aggression, circulating hormone profiles and aromatase (ARO) immunoreactivity in brain regions associated with aggressive or reproductive behaviours (paraventricular hypothalamic nucleus [PVN], periaqueductal gray [PAG] and ventral tegmental area [VTA]). Females that were responsive to SD photoperiods (SD-R) and LD females given timed melatonin injections (Mel-T) exhibited gonadal regression and reduced circulating E2 , but increased aggression and circulating dehydroepiandrosterone (DHEA). Furthermore, aggressive challenges differentially altered circulating hormone profiles across seasonal phenotypes; reproductively inactive females (ie, SD-R and Mel-T females) reduced circulating DHEA and T, but increased E2 after an aggressive interaction, whereas reproductively active females (ie, LD females, SD non-responder females and LD females given mis-timed melatonin injections) solely increased circulating E2 . Although no differences in neural ARO abundance were observed, LD and SD-R females showed distinct associations between ARO cell density and aggressive behaviour in the PVN, PAG and VTA. Taken together, these results suggest that melatonin increases non-breeding aggression by elevating circulating steroid metabolism after an aggressive encounter and by regulating behaviourally relevant neural circuits in a region-specific manner.

Putting it in Context: Linking Auditory Processing with Social Behavior Circuits in the Vertebrate Brain.

Context is critical to the adaptive value of communication. Sensory systems such as the auditory system represent an important juncture at which information on physiological state or social valence can be added to communicative information. However, the neural pathways that convey context to the auditory system are not well understood. The serotonergic system offers an excellent model to address these types of questions. Serotonin fluctuates in the mouse inferior colliculus (IC), an auditory midbrain region important for species-specific vocalizations, during specific social and non-social contexts. Furthermore, serotonin is an indicator of the valence of event-based changes within individual social interactions. We propose a model in which the brain's social behavior network serves as an afferent effector of the serotonergic dorsal raphe nucleus in order to gate contextual release of serotonin in the IC. Specifically, discrete vasopressinergic nuclei within the hypothalamus and extended amygdala that project to the dorsal raphe are functionally engaged during contexts in which serotonin fluctuates in the IC. Since serotonin strongly influences the responses of IC neurons to social vocalizations, this pathway could serve as a feedback loop whereby integrative social centers modulate their own sources of input. The end result of this feedback would be to produce a process that is geared, from sensory input to motor output, toward responding appropriately to a dynamic external world.

Exposure to advertisement calls of reproductive competitors activates vocal-acoustic and catecholaminergic neurons in the plainfin midshipman fish, Porichthys notatus.

While the neural circuitry and physiology of the auditory system is well studied among vertebrates, far less is known about how the auditory system interacts with other neural substrates to mediate behavioral responses to social acoustic signals. One species that has been the subject of intensive neuroethological investigation with regard to the production and perception of social acoustic signals is the plainfin midshipman fish, Porichthys notatus, in part because acoustic communication is essential to their reproductive behavior. Nesting male midshipman vocally court females by producing a long duration advertisement call. Females localize males by their advertisement call, spawn and deposit all their eggs in their mate's nest. As multiple courting males establish nests in close proximity to one another, the perception of another male's call may modulate individual calling behavior in competition for females. We tested the hypothesis that nesting males exposed to advertisement calls of other males would show elevated neural activity in auditory and vocal-acoustic brain centers as well as differential activation of catecholaminergic neurons compared to males exposed only to ambient noise. Experimental brains were then double labeled by immunofluorescence (-ir) for tyrosine hydroxylase (TH), an enzyme necessary for catecholamine synthesis, and cFos, an immediate-early gene product used as a marker for neural activation. Males exposed to other advertisement calls showed a significantly greater percentage of TH-ir cells colocalized with cFos-ir in the noradrenergic locus coeruleus and the dopaminergic periventricular posterior tuberculum, as well as increased numbers of cFos-ir neurons in several levels of the auditory and vocal-acoustic pathway. Increased activation of catecholaminergic neurons may serve to coordinate appropriate behavioral responses to male competitors. Additionally, these results implicate a role for specific catecholaminergic neuronal groups in auditory-driven social behavior in fishes, consistent with a conserved function in social acoustic behavior across vertebrates.

In vitro validation of new Fourier-domain optical coherence tomography.

AIMS: To validate the accuracy and evaluate the intra- and inter-observer variability of vascular measurements using novel Fourier-domain optical coherence tomography (FD-OCT) versus intravascular ultrasound (IVUS) in a coronary phantom model. METHODS AND RESULTS: A dedicated cylindrical phantom comprised of four sections with differing dimensions was used to compare images generated by five FD-OCT and five IVUS catheters. Each FD-OCT catheter was tested using three different consoles, generating 15 imaging pullbacks. Two independent experts, blinded to the phantom data, performed measurements. There were 180 FD-OCT and 60 IVUS cross-sectional measurements of mean lumen diameter (MeanLD), minimal lumen diameter (MLD), maximum lumen diameter (MaxLD) and lumen area (LA) at three points in each section. FD-OCT measurements had excellent correlations with IVUS (concordance correlation coefficient [CCC]: ≥0.9769 for MeanLD, LA or longitudinal length [LL]) and phantom dimensions (CCCs for FD-OCT: ≥0.9958 for MeanLD, LA or LL). FD-OCT measurements were larger than IVUS (p<0.0001), but showed less measurement errors compared to IVUS (p<0.0001). Moreover, FD-OCT caused less discrepancy between MaxLD and MLD versus IVUS (p<0.0001). Intra- and inter-observer variability was low for both FD-OCT (CCCs for MeanLD, LA and LL ≥0.9996) and IVUS (≥0.9935). Image catheter position did not influence FD-OCT measurements. CONCLUSIONS: FD-OCT was more accurate than IVUS and had similar high reproducibility to determine vascular dimensions in vitro. These results support the use of FD-OCT in the clinical setting.