Enhanced maternal behaviors in a mouse model of congenital blindness.

In mammals, mothering is one of the most important prosocial female behavior to promote survival, proper sensorimotor, and emotional development of the offspring. Different intrinsic and extrinsic factors can initiate and maintain these behaviors, such as hormonal, cerebral, and sensory changes. Infant cues also stimulate multisensory systems and orchestrate complex maternal responsiveness. To understand the maternal behavior driven by complex sensory interactions, it is necessary to comprehend the individual sensory systems by taking out other senses. An excellent model for investigating sensory regulation of maternal behavior is a murine model of congenital blindness, the ZRDBA mice, where both an anophthalmic and sighted mice are generated from the same litter. Therefore, this study aims to assess whether visual inputs are essential to driving maternal behaviors in mice. Maternal behaviors were assessed using three behavioral tests, including the pup retrieval test, the home cage maternal behavior test, and the maternal aggression test. Our results show that blind mothers (1) took less time to retrieve their offspring inside the nest, (2) spent more time nursing and licking their offspring in the second- and third-week postpartum, and (3) exhibited faster aggressive behaviors when exposed to an intruder male, compared to the sighted counterparts. This study provides evidence that congenitally blind mothers show more motivation to retrieve the pups, care, and protection towards their pups than sighted ones, likely due to a phenomenon of sensory compensation.

Quantifying neural efficiency and neural capacity across the brain during a working memory task using a quadratic model of neural-cognitive relationships.

Task-based functional magnetic resonance imaging (MRI) neuroimaging for the study of cognitive neuroscience provides insight into how the brain responds to increasing cognitive demands. Theoretical models of neural-cognitive relationships define neural efficiency and neural capacity as two parameters to describe the rate of gain of brain activity and the upper limits of the increases, respectively. Although qualitatively well described, there are limited discussions and demonstrations of estimating these parameters from data. The current work presents a method using a quadratic equation model of cognitive demands. The methods were applied to 21 healthy young adults while engaging in four levels of the verbal n-back working memory task (0, 1, 2 and 3-back). Measures of the area under the curve captured both linear and curvilinear responses to quantify the locations and amounts of task-related increases in brain activity. In addition, we calculated voxel-wise maps of neural efficiency and neural capacity. Results showed increases in brain activation in regions typically involved in working memory. The relationships between increasing cognitive demands and brain activity also differed across the brain within and between individuals, as indicated by differential neural efficiency and neural capacity values. This approach provides tools for evaluating current theories about the relationships between brain activity and cognition. Neural efficiency and neural capacity provide physiological measures of brain activity, which will help evaluate how age, disease and intervention processes affect brain activity. Finally, all presented methods are readily applicable using standard current software packages for neuroimaging.

Better Olfactory Performance and Larger Olfactory Bulbs in a Mouse Model of Congenital Blindness.

It is well established that early blindness results in enhancement of the remaining nonvisual sensory modalities accompanied by functional and anatomical brain plasticity. While auditory and tactile functions have been largely investigated, the results regarding olfactory functions remained less explored and less consistent. In the present study, we investigated olfactory function in blind mice using 3 tests: the buried food test, the olfactory threshold test, and the olfactory performance test. The results indicated better performance of blind mice in the buried food test and odor performance test while there was no difference in the olfactory threshold test. Using histological measurements, we also investigated if there was anatomical plasticity in the olfactory bulbs (OB), the most salient site for olfactory processing. The results indicated a larger volume of the OB driven by larger glomerular and granular layers in blind mice compared with sighted mice. Structural plasticity in the OB may underlie the enhanced olfactory performance in blind mice.

Smell training improves olfactory function and alters brain structure.

Training and repeated exposure to odorants leads to enhanced olfactory sensitivity. So far, the efficacy of intensive olfactory training on olfactory function in a healthy population and its underlying neurobiological basis remain poorly known. This study investigated the effects of a 6-week intensive and well-controlled olfactory training on olfactory function and brain structure/neuroplasticity. Thirty-six healthy young individuals were recruited and randomly distributed in three groups: (1) 12 participants underwent daily intensive olfactory training of at least 20 min that included an (a) odor intensity classification task, an (b) odor quality classification task and an (c) target odor detection task, (2) 12 participants underwent an equivalent visual control training, and (3) 12 control individuals did not participate in any training. Before and after the training period, all participants performed a series of olfactory tests and those from groups 1 and 2 underwent structural magnetic resonance (MR) imaging, from which we obtained measures such as cortical thickness and tissue density. Participants improved in the respectively trained tasks throughout the 6-weeks training period. Those who underwent olfactory training improved general olfactory function compared to control participants, especially in odor identification, thus showing intramodal transfer. Further, MR imaging analysis revealed that olfactory training led to increased cortical thickness in the right inferior frontal gyrus, the bilateral fusiform gyrus and the right entorhinal cortex. This research shows that intensive olfactory training can generally improve olfactory function and that this improvement is associated with changes in the structure of olfactory processing areas of the brain.

Development of Odor Hedonics: Experience-Dependent Ontogeny of Circuits Supporting Maternal and Predator Odor Responses in Rats.

UNLABELLED: A major component of perception is hedonic valence: perceiving stimuli as pleasant or unpleasant. Here, we used early olfactory experiences that shape odor preferences and aversions to explore developmental plasticity in circuits mediating odor hedonics. We used 2-deoxyglucose autoradiographic mapping of neural activity to identify circuits differentially activated by biologically relevant preferred and avoided odors across rat development. We then further probed this system by increasing or decreasing hedonic value. Using both region of interest and functional connectivity analyses, we identified regions within primary olfactory, amygdala/hippocampal, and prefrontal cortical networks that were activated differentially by maternal and male odors. Although some activated regions remained stable across development (postnatal days 7-23), there was a developmental emergence of others that resulted in an age-dependent elaboration of hedonic-response-specific circuitry despite stable behavioral responses (approach/avoidance) to the odors across age. Hedonic responses to these biologically important odors were modified through diet suppression of the maternal odor and co-rearing with a male. This allowed assessment of hedonic circuits in isolation of the specific odor quality and/or intensity. Early experience significantly modified odor-evoked circuitry in an age-dependent manner. For example, co-rearing with a male, which induced pup attraction to male odor, reduced activity in amygdala regions normally activated by the unfamiliar avoided male odor, making this region more consistent with maternal odor. Understanding the development of odor hedonics, particularly within the context of altered early life experience, provides insight into the development of sensory processes, food preferences, and the formation of social affiliations, among other behaviors. SIGNIFICANCE STATEMENT: Odor hedonic valence controls approach-avoidance behaviors, but also modulates ongoing behaviors ranging from food preferences and social affiliation with the caregiver to avoidance of predator odors. Experiences can shape hedonic valence. This study explored brain circuitry involved in odor hedonic encoding throughout development using maternal and predator odors and assessed the effects of early life experience on odor hedonic encoding by increasing/decreasing the hedonic value of these odors. Understanding the role of changing brain circuitry during development and its impact on behavioral function is critical for understanding sensory processing across development. These data converge with exciting literature on the brain's hedonic network and highlight the significant role of early life experience in shaping the neural networks of highly biologically relevant stimuli.

The response of newly born mice to odors of murine colostrum and milk: unconditionally attractive, conditionally discriminated.

It is a general rule that milk conveys chemosensory cues that are attractive to mammalian neonates. This study investigated whether compositional fluctuations in milk along lactation induce variations in newborn mouse pups' (Mus musculus, strain BALB/c) attraction to milk odor. Pups differing in suckling experience were exposed to the odor of milk sampled from females varying in lactational stage. Immediately after birth, suckling-inexperienced (P0) and suckling-experienced (P0suck ) pups were assayed in a series of paired-choice tests contrasting murine milk [of lactation days 0, 3, 15 (abridged L0, L3, L15, respectively)] and a blank (water) to evaluate olfactory detection and attraction of milk odor. Preference tests further paired these milk two-by-two to assess their relative attraction. Results showed first that P0 and P0suck pups detect and positively orient to any milk odor. When L0 is presented against L15 milk, P0 pups orient for a similar duration towards these odor stimuli, whereas P0suck pups spend more time toward the odor of L0 than of L15 milk. Finally, P0suck pups orient similarly to odors of L0 milk collected before/after the first suckling episode (L0 and L0suck , respectively), but the odor of L0 milk was more attractive than that of L3 milk. Thus, mouse pups' positive orientation toward the odors of murine colostrum (assumed to correspond to L0/L0suck milk) and later-lactation milk appears unconditional of previous suckling experience, whereas their ability to discriminate or display preference between milk differing in lactation stage appears conditional on postnatal exposure effects.

Orientation of newborn mice to lactating females: identifying biological substrates of semiochemical interest.

Among mammals, odor-based communication between females and infants is decisive for neonatal survival. So far, the nature of odor substrates involved in the localization of the mother and their nipples is unknown in mice. The present study aims: (1) to evaluate the specific attractive value of lactating females to newborn mice, (2) to localize the abdominal region that is most attractive to pups, and (3) to identify odor substrates that support such attraction. Results showed that 5-6-day-old mice roam preferentially over the abdomen of lactating females than the abdomen of non-lactating females. In lactating females, pups are more attracted to abdominal areas comprising nipples. The blend of odor substrates from nipples, as well as separate sources presumed to compose it, viz. milk, maternal saliva and pup saliva, were detectable and equivalently attractive to pups. The equivalent attraction of these different odor substrates may derive either from overlap in chemical constituents, or from associative learning during nursing.

How does a newly born mouse get to the nipple? Odor substrates eliciting first nipple grasping and sucking responses.

It is a mammalian female strategy to emit odor cues and signals that direct their inexperienced newborns to the nipple, and optimize their initial sucking success and, hence, viability. Here, natural odorous substrates that contribute to nipple grasping were investigated in mice, a species that has not been much scrutinized on this topic. The response of pups toward the nipples of lactating females (LF) versus nonlactating females (NLF) were first assessed right after watched birth, before and after the first suckling experience, and at 1 day old, after more extended suckling experience. It appeared that only nipples of LF induced grasping at these early ages, leading to take NLF as the baseline setting to present various odor substrates sampled from LF, viz. amniotic fluid, murine milk, LF saliva, pup saliva, LF urine, and an odorless control stimulus (water). Results indicate that: (1) only amniotic fluid and fresh milk induced nipple grasping before the first suckling experience; (2) LF saliva started inducing grasping after the first suckling experience; (3) pup saliva released grasping after 24-36 hr of suckling experience; finally (4) neither LF urine, nor water induced any nipple grasping. In conclusion, the activity of amniotic fluid and murine milk on neonatal pup behavior before any postnatal suckling experience suggests that either prenatal learning and/or predisposed olfactory mechanisms do operate, while the behavioral activation due to maternal and infantile salivas clearly depends on postnatal exposure.

Effects of Congenital Blindness on Ultrasonic Vocalizations and Social Behaviors in the ZRDBA Mouse.

Mice produce ultrasonic vocalizations (USVs) at different ages and social contexts, including maternal-pup separation, social play in juveniles, social interactions, and mating in adults. The USVs' recording can be used as an index of sensory detection, internal state, and social motivation. While sensory deprivation may alter USVs' emission and some social behaviors in deaf and anosmic rodents, little is known about the effects of visual deprivation in rodents. This longitudinal study aimed to assess acoustic communication and social behaviors using a mouse model of congenital blindness. Anophthalmic and sighted mice were assayed to a series of behavioral tests at three different ages, namely, the maternal isolation-induced pup USV test and the home odor discrimination and preference test on postnatal day (PND) 7, the juvenile social test on PND 30-35, and the female urine-induced USVs and scent-marking behavior at 2-3 months. Our results evidenced that (1) at PND 7, USVs' total number between both groups was similar, all mice vocalized less during the second isolation period than the first period, and both phenotypes showed similar discrimination and preference, favoring exploration of the home bedding odor; (2) at PND 30-35, anophthalmic mice engaged less in social behaviors in the juvenile play test than sighted ones, but the number of total USVs produced is not affected; and (3) at adulthood, when exposed to a female urine spot, anophthalmic male mice displayed faster responses in terms of USVs' emission and sniffing behavior, associated with a longer time spent exploring the female urinary odor. Interestingly, acoustic behavior in the pups and adults was correlated in sighted mice only. Together, our study reveals that congenital visual deprivation had no effect on the number of USVs emitted in the pups and juveniles, but affected the USVs' emission in the adult male and impacted the social behavior in juvenile and adult mice.

Anxiety and Depression Assessments in a Mouse Model of Congenital Blindness.

Previous studies have reported that visual impairment can affect the quality of life leading to mental health disorders. This study aimed to investigate associations between vision impairment, depression and anxiety using a mouse model of congenital blindness. We phenotyped 15 anophthalmic and 17 sighted adult mice in a battery of tests for anxiety and depression-like behaviors: open field test, elevated plus maze, coated test, splash test, and forced swim test. We found that: (1) Anxiety levels of the anophthalmic mice were significantly lower when compared with sighted mice, (2) Anophthalmic mice displayed more exploratory behaviors in a new environment than the sighted one, and (3) Depression levels between those groups were similar. In conclusion, this behavioral study showed that early visual deprivation lowers anxiety levels, associated with heightened exploratory activity, but does not induce depressive symptoms in a mouse model of congenital blindness, underlying several behavioral adaptations.

Pain Hypersensitivity is Associated with Increased Amygdala Volume and c-Fos Immunoreactivity in Anophthalmic Mice.

It is well established that early blindness results in brain plasticity and behavioral changes in both humans and animals. However, only a few studies have examined the effects of blindness on pain perception. In these studies, pain hypersensitivity was reported in early, but not late, blind humans. The underlying mechanisms remain unclear, but considering its key role in pain perception and modulation, the amygdala may contribute to this pain hypersensitivity. The first aim of this study was to develop an animal model of early blindness to examine the effects of blindness on pain perception. A mouse cross was therefore developed (ZRDBA mice), in which half of the animals are born sighted and half are born anophthalmic, allowing comparisons between blind and sighted mice with the same genetic background. The second aim of the present study was to examine mechanical and thermal pain thresholds as well as pain behaviors and pain-related c-Fos immunoreactivity induced by the formalin test in the amygdalas of blind and sighted mice. Group differences in amygdala volume were also assessed histologically. Blind mice exhibited lower mechanical and thermal pain thresholds and more pain behaviors during the acute phase of the formalin test, compared with sighted mice. Moreover, pain hypersensitivity during the formalin test was associated with increased c-Fos immunoreactivity in the amygdala. Furthermore, amygdala volume was larger bilaterally in blind compared with sighted mice. These results indicate that congenitally blind mice show pain hypersensitivity like early blind individuals and suggest that this is due in part to plasticity in the amygdala.

Neurobehavioral assessment of maternal odor in developing rat pups: implications for social buffering.

Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother's social buffering of the infant is one of the more robust examples; yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-deoxyglucose (2-DG) and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (Basolateral Amygdala [BLA]), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC, or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering.

Newborns prefer the odor of milk and nipples from females matched in lactation age: Comparison of two mouse strains.

Newborn mice are attracted to mammary odor cues carried in murine milk and nipple secretions. However, murine milk odor is not equally attractive along lactation. The present study focuses on the differential response of 2day-old mouse pups of C57Bl/6 (C) and Balb/C (B) strains to the odor of milk (Experiment 1) and nipples (Experiment 2) that are matched/unmatched in terms of pup's age or strain. In Experiment 1, C and B pups were tested in a series of tests simultaneously opposing either murine milk and a blank (water), or two milks collected in early and late lactation (lactation days 2 and 15, respectively) from females belonging to their own or the other strain. Results showed that C and B pups were attracted to the odor of the different milks regardless of the lactation age and the strain of the donor female. Nevertheless, C and B pups preferred the odor conveyed by early- than late-lactation milk of either strain. Moreover, early-lactation milk from C females was more attractive than early-lactation milk from B females for pups of either strain. In Experiment 2, differential nipple grasping response of C and B pups was measured when they were exposed to nipples of females in early or late lactation. The proportion of C pups that grasped a nipple was greater when they were exposed to a nipple in early lactation regardless of the strain of the donor females, whereas the proportion of B pups that grasped a nipple was greater when they were exposed to a nipple in early lactation, but only from own strain. Thus, newborn mice prefer the odor of milk and nipples from females that are matched in lactation age. This result is discussed in terms of reciprocally adaptive mechanisms between lactating females and their newborn offspring.

Testing smell when it is really vital: behavioral assays of social odors in the neonatal mouse.

The initial interactions of mouse newborns with their mother are crucial for their survival. These interactions rapidly end in the pups reaching nipples and getting milk. While we realize that olfaction is clearly prevailing in the success of these first suckling episodes, we still understand little about the nature and range of the natural odorants involved. Here we non-exhaustively describe some experimental principles and methods to assay the behavior of newly born and infant mice exposed to different odor stimuli from conspecifics. Testing neonatal and young mice with chemostimuli which they are evolutionarily or developmentally canalized to detect may be a productive way to trace unanticipated odor signals. Moreover, testing neonates also may also lead to characterize unsuspected strategies of murine females to produce and release odor messages.

What is the emotional core of the multidimensional Machiavellian personality trait?

Machiavellianism is a personality trait characterized by interpersonal manipulation and associated with specific patterns of emotional and social cognition skills. The aim of this study was to investigate its socio-cognitive characteristics by determining its association and predictors on the basis of a multidimensional approach to Machiavellianism. We used Mach IV scale to assess "Machiavellian Intelligence" skill of participants (Christie and Geis, 1970). It includes three subscales that are (1) the use of deceit in interpersonal relationships, (2) a cynical view of human nature and (3) the lack of morality. Associations were found between Machiavellianism and low levels of empathy and affective ToM, and high levels of alexithymia, anhedonia, depression, and anxiety. These associations were observed in varying proportions depending on the three subscales of Machiavellianism. The addition of anhedonia and trait-anxiety to the concepts of empathy and alexithymia made it possible to gain a better understanding of the emotional core of Machiavellianism. These findings are discussed in the light of developmental and adaptive perspectives.

An odor timer in milk? Synchrony in the odor of milk effluvium and neonatal chemosensation in the mouse.

Mammalian newborns exhibit avid responsiveness to odor compounds emanating from conspecific milk. Milk is however developmentally heterogeneous in composition as a function of both evolved constraints and offspring demand. The present study aimed to verify whether milk odor attractivity for neonates is equally distributed along lactation in Mus musculus (Balb-c strain). Therefore, we exposed pups varying in age to milk samples collected from females in different lactational stages. The pups were assayed at postnatal days 2 (P2), 6 (P6) and 15 (P15) in a series of paired-choice tests opposing either murine milk and a blank (water), or two samples of milk collected in different stages of lactation [lactation days 2 (L2), 6 (L6), and 15 L15)]. Pups of any age were able to detect, and were attracted to, the odor of the different milk. When milk from different lactational stages were simultaneously presented, P2 pups oriented for a similar duration to the odors of L2 and of L6 milk, but significantly less to the odor of L15 milk. Next, P6 pups roamed equivalently over L2 and L6 milk odors, but still less over the odor of L15 milk. Finally, P15 pups explored as much L15 milk odor as the odors of both L2 and L6 milk. This developmental shift in milk attractivity is discussed in terms of changing chemosensory properties of milk and of shifting chemosensory abilities/experience of pups.