Solitary Mammals Provide an Animal Model for Autism Spectrum Disorders

The APA journal, "Journal of Comparative Psychology," just published an article that I wrote titled:

"Solitary Mammals Provide an Animal Model for Autism Spectrum Disorders."

Reser, J. E. (2013, November 4). Solitary Mammals Provide an Animal Model for Autism

Spectrum Disorders. Journal of Comparative Psychology. Advance online publication. doi:

10.1037/a0034519

The original manuscript can be found here:

http://www.jaredreser.com/cognitiveparsimony/animalmodel.html.

A related article that I wrote on the "solitary forager" hypothesis of autism can be found here:

http://www.epjournal.net/wp-content/uploads/EP09207238.pdf

Below are select portions of the abstract, introduction and conclusion:

Abstract:

Species of solitary mammals are known to exhibit specialized, neurological adaptations that prepare them to focus working memory on food procurement and survival rather than on social interaction. Solitary and nonmonogamous mammals, that do not form strong social bonds, have been documented to exhibit behaviors and biomarkers that are similar to endophenotypes in autism. Both individuals on the autism spectrum and certain solitary mammals have been reported to be low on measures of affiliative need, bodily expressiveness, bonding and attachment, direct and shared gazing, emotional engagement, conspecific recognition, partner preference, separation distress, and social approach behavior. Solitary mammals also exhibit certain biomarkers that are characteristic of autism including: diminished oxytocin and vasopressin signaling, dysregulation of the endogenous opioid system, increased HPA activity to social encounters, and reduced HPA activity to separation and isolation. The extent of these similarities suggests that solitary mammals may offer a useful model of autism spectrum disorders, and an opportunity for investigating genetic and epigenetic, etiological factors. If the brain in autism can be shown to exhibit distinct homologous or homoplastic similarities to the brains of solitary animals, it will reveal that they may be central to the phenotype and should be targeted for further investigation. Research into the neurological, cellular and molecular basis of these specializations in other mammals may provide insight for behavioral analysis, communication intervention, and psychopharmacology for autism.

Introduction:

Autism is a developmental disorder defined by behavioral symptoms across three general areas: social reciprocity, communication, and restricted and repetitive interests (DSM IV TR). It is diagnosed through behavioral observation using standardized tools as well as clinical judgment (Piven, 2000). The diagnostic indicators are behavioral symptoms rather than definitive neurological markers. Proposed biomarkers include gene expression profiling, proteomic profiling, metabolomic profiling, head size, brain structure, neurotransmission and eye movement (Walsh et al., 2011). Multiple etiologies are involved in autism and autism spectrum disorders (ASDs), including genetic susceptibility, multigenic interactions, and interactions between genetic and environmental factors (Cantor, 2009). Because of the broad range of biomarkers and etiological factors, well-defined animal models that can recapitulate core symptoms of the disorder are essential for research into the nature of the neurological aberrations. Currently, mouse models are the most widely utilized because of the extensive knowledgebase available for mouse genetics and neurology and because of the availability of detailed behavioral phenotyping data available for many mouse strains (Halladay et al., 2009).

Rodent models of autism typically involve mice with specific lesions, mice that are genetically engineered to carry certain genes, or panels of inbred mouse strains carrying naturally occurring genetic polymorphisms. Advances have included the establishment and evaluation of mouse models capable of reflecting disease symptoms such as impaired social interaction, communication deficits and repetitive behaviors. Large scale datasets and biobanks have linked multiple genes to autism spectrum disorders, and genetic linkage and association studies in humans have begun to inform the design of mouse models. Transgenic rodent mutants with deletions, truncations and overexpression of these autism candidate genes have helped to model the disorder (Moy & Nadler, 2008). However, the rodents used for these models are primarily social animals that are engineered to have symptoms characteristic of social deficits. The present article attempts to place emphasis on the potential importance of naturally occurring phenotypes found in solitary species in modeling autism. There is a large knowledgebase in zoology and behavioral neuroscience of naturally existing variation in social capacities found between mammalian species that can be harnessed as a tool to inform the development of future animal models and to provide insight into the biology of autism.

Most animals, many mammals and several species of primates are solitary (Alcock, 2001). Solitary species are known to have specialized, behavioral adaptations that prepare them mentally to live alone (Decety, 2011). These behavioral adaptations have been shown to have neural underpinnings (Young, 2009). Adjustments to neural social circuits and associated neurotransmitters, neuromodulators and their receptors, fine-tune solitary animals to direct cognition toward foraging and self-preservation rather than on interaction with conspecifics (Alcock, 2001). Not all solitary mammals exhibit the same suite of adjustments. This is because individual species respond to diverse social concerns particular to their unique environments. There does, however, seem to be a large amount of convergence in many of these adjustments (Adolfs, 2001). Social neuroscientists have begun to elucidate specific neurological pathways that underlie specializations involved in prosocial behavior, attachment and bonding. Researchers are also beginning to compare the pathways found in social animals with those in solitary animals (Shapiro & Insel, 1990), and identify traits that correlate with group size and social necessity (Dunbar, 1988; 1998). Even though this research is in its nascent stages and the pathways involved are currently not well-resolved, continued experimental research may have important implications for autism spectrum disorders (ASD) because individuals on the autism spectrum share a variety of traits with solitary species (Reser, 2011a; 2011b). In an effort to promote this comparative approach, the present article will review literature that points to comparable traits.

           Our understanding of the “social nervous system” has been driven by studies analyzing specific biological markers in species that parent, species that are socially monogamous, species capable of developing extended families, and those capable of selective social camaraderie (Porges & Carter, 2010). Comparisons of the species-typical mating and affiliative strategies between the socially monogamous prairie vole (Microtus ochrogaster) and the closely related but nonmonogamous (promiscuous or polygamous) montane vole (Microtus montanus), has served as the primary model for the mapping of the neurocircuitry of social behavior in mammals (Carter et al., 1995). These voles have been closely studied, and exhibit divergent traits in the neuroscience of bonding and attachment. These and other closely related, but socially discrepant pairs of species will be discussed in an effort to build a comparative paradigm.

Individuals on the autism spectrum exhibit both behaviors and biological markers that are common in solitary and nonmonagomous mammals (Reser, 2011). Both solitary mammals and autistic individuals have been reported to demonstrate lower measures of: affiliative need, bodily expressiveness, bonding and attachment, conspecific recognition, emotional engagement, gregariousness, partner preference, separation distress and social approach behavior. Individuals with autism also exhibit certain biological markers that are characteristic of solitary mammals including: diminished oxytocin and vasopressin action, dysregulation of the endogenous opioid system, increased HPA activity to social events, and reduced HPA activity to separation, and isolation owing to anomalies in vagal tone, and parasympathetic response (some of these mechanisms may be ontogenetically prior to others). See Tables 1 and 2 below for matched comparisons between: A) neurotypical humans and humans with autism; and B) the nonmonogamous montane vole, and the monogamous prairie vole. Are the similarities in these shared behaviors sufficient to warrant the pursuit of a solitary mammal model of autism? Before this question can be answered these purported similarities must be investigated in a variety of species with differing bonding and attachment strategies.

Table 1

Behavioral Predispositions in Autism and Montane Voles

Reduced Behaviors	Individuals with Autism Relative to Those Without	Montane Voles Relative to Prairie Voles
Affiliative need, gregariousness and social approach	(Mundy, 1995; Emre et al., 2009; Baron-Cohen et al., 2000)	(Lim et al., 2004; Shapiro & Insel, 1990)
Bodily expressiveness and communicativeness	(Yirmija et al., 1989; Begeer et al., 2009; Peppe, 2007)	(Marler, 1968; Hammock and Young, 2006)
Bonding and attachment	(Sigman & Ungerer, 1984; Rutgers et al., 2004)	(Marler, 1968; Hammock and Young, 2006)
Conspecific recognition	(Dalton et al., 2005; Pierce & Redcay, 2008)	(Lim et al., 2004; Young, 2002)
Social preference	(Buitelaar, 1995; Depue & Morrone-Strupinsky, 2005)	(Lim et al., 2004; Young, 2009)

Table 2

Neurological Presentations in Autism and Montane Voles

Presentations	Humans with Autism	Montane Relative to Prairie Voles
Reduced action of oxytocin and vasopressin	(Green et al., 2001; Hollander et al., 2003)	(Marler, 1968;  Shapiro and Insel, 1990)
Dysregulation of the endogenous opioid system	(Gilberg, 1995; Machin & Dunbar, 2011)	(Shapiro et al., 1989)
Anomalies in vagal tone and parasympathetic response	(Porges & Carter, 2010; Porges, 2005)	(Grippo et al., 2007; 2008; Shapiro & Insel, 2004)
HPA hyperactivity in social situations	(Baron-Cohen et al., 2000; Sahley & Panksepp, 1986)	(Shapiro and Insel, 1990; Hammock and Young, 2006)

 
 
 

There are currently no animal models that reflect the entire range of behavioral and neurological phenotypes in autism; however, some researchers have advised that studies into the neurobiology of normal social cognition may provide clarification for understanding the mechanisms responsible for autism (Hammock and Young, 2006). This article extends this argument, advising that studies into the neurobiology of solitary cognition may provide further insight and clarification. Regardless of whether the similarities between the brains of solitary/nonmonogamous mammals and individuals on the autism spectrum are coincidental or are partly due to adaptive convergence to similar ecological demands (as proposed and outlined in Reser, 2011a), they may help to elucidate the neurobiological and molecular underpinnings of ASD.

Hammock and Young (2006) posit that:

“Basic research into ethologically relevant behavior of the prairie vole has allowed us to gain insight into some of the underlying neural and genetic mechanisms of social-bonding behavior in mammals. Humans may share some of these mechanisms and when these mechanisms are disrupted, either by genetic, environmental or interactive causes, extreme phenotypes such as autism may be revealed. These studies illustrate the power of the comparative neuroethological approach for understanding human neurobiology and suggest that examining the neurobiological bases of complex social behavior in divergent species is a valuable approach to gaining insights into human pathologies.”

Mammals that Forage Solitarily

Some animal species are obligately social, some are obligately solitary, and others are facultatively social, and can transition between social and solitary lifestyles. Species that are obligately social form groups even under very low population densities (Bothman & Walker, 1999), whereas some species like whistling rats (Paratomys brantsii) maintain solitary living even under very high population densities (Jackson, 1999). Obligate solitary living is rare in birds, but common in mammals, reptiles, amphibians, and invertebrates. Among the many mammals that have been categorized as solitary are well-known animals such as armadillos, opossums, orangutans, red pandas, red squirrels, Tasmanian devils, as well as most bears, cougars, tigers, and skunks. See Table 3 below for a more extensive list that includes a diverse assortment of mammals from orders including: primates, lagomorpha, rodentia, carnivora, insectivora, artiodactyla, perissodactyla, soricomorpha, xenarthra, and also marsupials and monotremes.

  Table 3:
Abridged List of Solitary Mammals
Armadillo, Baikal seal, Bamboo rat, Bear, Black Rhinoceros, Black-footed Cat, Blind mole rat, Brown-throated Sloth, Bushbuck, Bushy-tailed Opossum, Clouded Leopard, Coast Mole, Cougar, Dusky-Footed Woodrat, Eastern Pygmy Possum, European Mink, European Polecat, Fishing Cat, Four-horned Antelope, Four-toed Hedgehog, Giant Anteater, Grizzly bear, Hog-nosed skunk, Honey Badger, Jaguar, Japanese Hare, Javan Rhinoceros, Lemming Leopard, Maned Sloth, Marbled Polecat, Marten, Mountain Weasel, Montane Vole, Meadow Vole, Musk deer, Neotropical Otter, Northern Bettong, Opossum, Orangutan, Paca, Philippine Mouse-deer, Philippine Tarsier, Polar bear, Pudú, Red Brocket, Red Panda, Red Squirrel, Rhinoceros, Ringed seal, Scaly-tailed Possum, Short-beaked Echidna, Siberian chipmunk, Skunk, Solenodon, Southern Tamandua, Spotted skunk, Steppe Polecat, Striped Hog-nosed Skunk, Striped Polecat, Sumatran Rhinoceros, Tapeti, Tasmanian Devil, Tiger, Vagrant Shrew, Water deer, Zokor

Behavioral genetics has demonstrated that both social (subsocial, parasocial, presocial, eusocial etc.) and asocial tendencies have both genetic and neural underpinnings (Trivers, 1985). Furthermore, these traits can show considerable variability both between and within animal species (Frank, 1998). Significant intraspecific variation in social propensities has been observed in more than a hundred vertebrate species (Lott, 1991). It is not clear if the variation within species is due to genetic differences between individuals, differential responses to environmental circumstances, or gene-environment interactions. Likewise, it is not clear why there might be variation in social propensities and abilities within our own species (Baron-Cohen, 1995). However, it is thought that much variation between species is genetic. Perhaps both intra and interspecific diversity can be utilized to investigate the autism spectrum; however, the data concerning interspecific diversity is currently much stronger. Even closely related species can have vastly divergent social predispositions. In fact, phylogenetic inertia is thought to be strong for general physiology but not for social behavior, i.e., closely related species can have very different social organization if they live in different habitats or eat different foods (Zuk, 2002).

Placed together in a large room, several species of rodents, such as nonmonagamous montane voles, are content to be loners, and will spread out uniformly attempting to maximize the distance between themselves and their conspecifics. Social rodents like monogamous prairie voles, if placed in the same room, will prefer to huddle together and affiliate in close proximity (Shapiro and Insel, 1990). It is thought that the wide discrepancy in social behavior between these voles reflects adaptation to two very different physical and social environments (Adolfs, 2001). In prairie and pine voles, the males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form pair bonds and only the females take part in rearing the young. This is true in the wild and in captivity. It is believed that this diversity in behavior is maintained by selection favoring one of two male spatial/paternity strategies: 1) maintain a small home range and actively defend the female that you are monogamous with from other males (breeder); or 2) maximize range by wandering in order to maximize the rate at which unguarded females are encountered (roamer) (Phelps, 2010).

Nonmonogamous montane and meadow voles do not show partner preferences that prairie and pine voles do after experimentally induced pair-bonds are instigated by cohabitation (Lim et al., 2004). This may be likened to the situation in autism where social bonding and secure attachment behavior is diminished (Sigman & Ungerer, 1984). Pups of the monogamous prairie vole, but not the nonmonogamous montane vole, show a robust stress response to maternal separation along with increased vocalization and increased serum corticosterone levels (Shapiro and Insel, 1990). This behavioral pattern is highly analogous to the diminished separation distress evident in autistic infants and children. In fact, children with autism show diminished (but existent) preferential proximity seeking and reunion behavior in the Strange Situation Test and other measures (Buitelaar, 1995; Naber et al., 2008).

Because of small size and easy maintenance in the laboratory, the neurobiology of the social differences between these two species of vole has been carefully examined. The differences are thought to be largely governed by the regulation of the neuromodulators oxytocin (OXT) and vasopressin (AVP) (Churchland, 2011). In fact, neuropeptides like oxytocin, vasopressin and endogenous opioids are known to regulate complex social behaviors in conjunction with monoaminergic neurotransmitter systems (Miller, 2005). Interestingly, the same neuropeptides have been shown to be affected in autism (Gilberg, 1995; Green et al., 2001; Hollander et al., 2003; Machin & Dunbar, 2011). In fact, preliminary data suggests that allelic variants of genes necessary for the development of parental and affiliative behaviors in other species (especially the genes for the oxytocin and prolactin receptors) are associated with ASD (Yrigollen et al., 2008).

It will be interesting to perform further comparative analyses, but it is not completely clear which genes or which brain systems should be interrogated. A relevant model of neurobiological regulation of affiliation in mammals (Depue & Morrone-Strupinsky, 2005) has suggested that dopamine plays an important role in incentive-reward motivational processes associated with the appetitive phase of affiliation, endogenous opioids are involved in the consummatory phase of socialization, and oxytocin and vasopressin enhance the perception and memory of affiliative stimuli. To begin to make the appropriate comparisons, let us first take a look at the role of oxytocin signaling in nonmonogamous rodents, and in autism.

 

Oxytocin Signaling

Oxytocin is a peptide hormone and neuromodulator involved in reproduction, social recognition, and pair-bonding in mammals. Animal species that rely on pair-bonds and social attachment exhibit higher levels of plasma oxytocin, especially when it is behaviorally relevant, like during monogamous sex, childbirth, and lactation (Campbell, 2007). Not surprisingly, interspecific, seasonal and reproductive variation in oxytocin concentrations have been attributed adaptive significance. High levels are associated with mating, continued proximity, trust, and pair-bonding in a large number of mammals (Adolfs, 2001). Oxytocin is capable of down-regulating or buffering the response to stressors, especially social ones (acting at the level of the hypothalamus, among other areas). It is released during positive social interactions, and appears to facilitate capacity for being trusting, and socially perceptive (Porges & Carter, 2010). Oxytocin knockout mice show deficiencies in social recognition and social memory, and also in the ability to manage emotional reactivity due to stress (Takayanagi et al., 2005; Pederson et al., 2006).

After being synthesized in magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus, and processed along axonal projections to the posterior lobe of the pituitary, OXT and AVP are released into the extracellular space resulting in both local action and diffusion throughout the brain. OXT and AVP are also synthesized by parvocellular neurons of the hypothalamus, and from here travel directly, via hypothalamic projections, to different brain areas including the amygdala, hippocampus, striatum, suprachiasmatic nucleus, bed nucleus of the stria terminalis, and brainstem where they take different actions, dependent on the receptors they bind to. It is not clear if the areas that synthesize, process and distribute OXT and AVP are affected in autism or in solitary animals although this should be a topic of future research. It is known that the anatomical sites of oxytocin synthesis and their projections are highly conserved in mammalian species (Hammock and Young, 2006), but their quantitative properties may be divergent. On the other hand, there are significant differences in oxytocin receptor distribution patterns between monogamous and nonmonogamous mammals.

Prairie voles and montane voles have very different oxytocin receptor profiles. The montane vole, relative to the prairie vole, has a much smaller number of receptors in the brain for oxytocin and unlike the amorous prairie voles, they do not form pair-bonds (Marler, 1968). The montane voles have fewer receptors, and thus are less responsive to oxytocin, making them more wary, suspicious and more easily frightened of other members of their species (Marler, 1968).

When the two are compared, monogamous species have higher densities of oxytocin receptors in the caudate, putamen, amygdala, orbitofrontal cortex and nucleus accumbens (Hammock and Young, 2006).  This may indicate that these brain regions, and their quality of oxytocin receptivity should be attended to in autism. The shell region of the nucleus accumbens is especially abundant in oxytocin receptors in socially monogamous species and prairie voles but not in nonmonogamous voles (Insel, 2010). Oxytocin receptor antagonists applied directly to the nucleus accumbens of female prairie voles inhibit mating-induced partner preference formation, indicating that activation of oxytocin receptors in this area of the brain is necessary for bonding and attachment (Young et al., 2001). Other nonmonagamous species such as marmoset monkeys, rhesus monkeys, titi monkeys, the California deer mouse and the white-footed mouse, have OXT and AVP receptor distributions that are highly similar to that of the montane vole (Bales et al., 2007; Wang et al., 1997). These comparisons suggest that autism research should be focused on the nucleus accumbens and its role in social motivation. It would be interesting to compare the details of oxytocin action, such as receptor number and distribution pattern, in solitary animals with that of people with autism but again this research has not been done. The comparable data about receptor density and distribution in humans has not been determined because injection methods to tag receptors cannot be done in living humans for ethical reasons, and do not yield results when performed on the brains of cadavers.

Results interpreted as supporting the hypothesis that baseline cerebrospinal fluid (CSF) oxytocin concentrations are related to species-typical social/affective behavior patterns comes from comparisons between bonnet macaques (Macaca radiata) and pigtail macaques (Macaca nemestrina). The bonnet macaques, which have significantly higher levels of CSF concentrations of oxytocin when laboratory-born than the pigtail macaques, are described as gregarious affiliative and affectively stable, while pigtail macaques are described as socially distant and temperamentally unstable (Rosenblum et al., 2002). Furthermore, the pigtail macaques exhibited elevations in CSF corticotropin releasing factor, elevations of which promote social vigilance in both solitary and territorial mammals. Within a species, the early environment may play a role. When rhesus macaques (Macaca mulatta) are separated from their mothers at birth and reared with peers in a small cage they develop a wide range of behavioral abnormalities that have been associated with autistic symptoms. These monkeys exhibit low affiliation, high aggression, and high self-directed and repetitive activities. These genetically very social monkeys also had a significantly lower concentration of CSF oxytocin (Winslow et al., 2003).

Oxytocin, the neuropeptide thought to enhance social learning, social expressiveness, direct eye gaze, and the ability to remember faces in humans (Savaskan et al., 2008), is reduced in the blood plasma of autism subjects. Diminished circulating levels of oxytocin may play a large role in retuning multiple social brain modules in autism and increasing fear and avoidance responses to social stimuli (Green et al., 2001). It has been shown that intravenous oxytocin produces a significant reduction in stereotypic behaviors in adult autism subjects and increases empathy and generosity in people without autism (Hollander et al., 2003). After treatment with intranasally inhaled oxytocin, autistic patients have been reported to exhibit more appropriate social behavior (Andari et al., 2010), increased attention to the eye region of faces (Andari et al., 2010), increased emotion recognition (Guastella et al., 2010), diminished repetitive behavior (Kosfeld et al., 2005), and diminished social fear (Kirsch et al., 2005). Likewise, oxytocin infusions into the brain increase side-by-side contact and decreased aggressive behavior in female prairie voles (Witt et al., 1990), increased social contact in male rats (Witt et al., 1992), and in squirrel monkeys (Winslow & Insel, 1991). While this research is promising, further clinical trials are necessary to demonstrate potential benefits and side-effects in the treatment of autism (Bartz & Hollander, 2008).

Humans and all eutherian mammals have only one receptor for oxytocin, OXTR, but humans have several alleles for the receptor which differ in their binding effectiveness. Individuals homozygous for the “G” allele (which produces the high affinity receptor) when compared to carriers of the “A” allele, show higher empathy, lower overall stress response, as well as lower prevalence of autism (Rodrigues et al., 2009). Two single nucleotide polymorphisms in the third intron of the oxytocin receptor have emerged as candidate genes for autism. In fact, several studies have shown that these polymorphisms were overtransmitted by families to offspring with ASD (Wu et al., 2005; Wermter et al., 2010). Other genes seem to be involved as well. Recent work on CD38, a transmembrane protein that is involved in oxytocin secretion in the brain, has shown that several genetic variants of the gene show a significant association with high functioning autism (Munesue et al., 2010). Although several studies point to function of the oxytocin receptor (Jacob et al., 2007; Wermter et al., 2009), the underlying problem with oxytocin signaling in autism remains unclear.

Vasopressin Signaling

Arginine vasopressin is a peptide hormone found in most mammals that plays a key role in homeostasis and the regulation of water, glucose and salts in the blood. Stored in vesicles in the posterior pituitary, most AVP is released into the bloodstream, although some AVP is released directly into the brain where it plays a significant role in social behavior and bonding. Humans and all eutherian mammals have three receptors vasopressin, AVP receptor 1A (AVPR1A), AVP receptor 1B and AVP receptor 2. Experimental studies in several species have indicated that the precise distribution of vasopressin receptors in the brain is associated with species-typical patterns of social behavior. Specifically, there are consistent differences between monogamous and nonmonogamous voles in the distribution of AVP receptors and the distribution of AVP containing axons (Young, 2009). AVP release during social interaction and mating in prairie voles leads to increased activation of brain areas with high levels of AVP receptors, such as the ventral pallidum. High density of receptors in the ventral pallidum is also found in the monogamous marmoset, evincing convergent evolution among rodents and primates. Activation of the pallidum, a key area in mammalian reward circuitry, is thought to reinforce affiliative behavior leading to conditioned partner preference, and initiation of pair-bonding (Pitkow et al., 2001).

In male prairie voles, infusions of vasopressin directly into the brain facilitate partner preference formation and receptor antagonists block it (Winslow et al., 1993). Altering receptor density also makes a difference. Experimentally increasing the vasopressin receptor (V1aR) levels in the ventral pallidum of nonmonogamous meadow voles using the injection of a viral vector directly in the ventral pallidum resulted in the formation of strong partner preferences. Hammock and Young (2006) describe this experiment in the following way: “Therefore, even though these two species diverged long ago, this simple change in the expression of a single gene replicated a hypothetical evolutionary event that may have ultimately led to the development of monogamy.”

Vasopressin receptors in the lateral septum (which projects directly to the nucleus accumbens) have been shown, by studies using site-specific injections of a V1aR-specific antagonist, to be critical for social recognition in male mice (Bielsky et al., 2005). Further, these authors found that a viral vector causing reexpression of V1aR in the lateral septum of V1aR knockout mice resulted in a complete rescue of social recognition. Knowledge of the role of the ventral pallidum, the lateral septum and the nucleus accumbens in this circuit offers clues as to where to look and what brain areas to target in autism. In fact, the receptivity of these areas to vasopressin in autism remains undefined. These findings further substantiate the importance of attaining receptor distribution profiles in autism so that specific brain areas and their receptors can be manipulated for therapeutic purposes.

There is also evidence for a role of the gene that codes for the human vasopressin receptor, AVPR1A, in ASD. This evidence comes from genetic studies of the polymorphic microsatellite repeats in the 5’ flanking region of the gene (3,625 base pairs upstream of the transcription start site of AVPR1A). Of these repeats, overtransmission of RS3 and undertransmission of RS1 has been associated with ASD (Yirmiya et al., 2006; Wassink et al., 2004). Fascinatingly, similar microsatellite repeats have also been found in avpr1a in prairie voles and have been viewed as instrumental in regulating social behavior. Some, but not all studies have found an association of these repeats with social behaviors in voles (Mabry et al., 2011; Hammock & Young, 2005). King (1994) has suggested that instability of microsatellite sequences serves as a kind of evolutionary tuning knob (King, 1994). Hammock and Young have done extensive experimentation suggesting that the AVPR1A locus may be such a tuning knob, while relating their findings to autism (2005).

 

Discussion

This review has attempted, in an exploratory manner, to consider parallels in neurophysiology between ASD and solitary mammals. Preliminary comparative studies juxtaposing the neurobiology of social mammals with that of solitary mammals have been done, but the pertinent comparisons with autism have only begun. The review suggests that basic and translational research into social cognition in solitary mammals, and the brain alterations that underlie it, could lead to advancements in understanding and ultimately treating autism. The pertinent literature also seems to suggest that research into the neurophysiology of solitary mammals may contribute to the identification of more specific biomarkers, and the development of more precise animal models. The similarities noted here may be numerous and fine-grained enough to suggest that they are not superficial or coincidental. The extent to which these animal studies can be directly extrapolated to autism is very unclear though.

This line of research points to four major dichotomies that might help to model autism, listed in Table 4 below. There is a monogamous/nonmonogamous dichotomy; a group/solitary dichotomy; and a domestic/wild dichotomy. There may also be a relevant female/male dichotomy as well as there is evidence of significant sexual dimorphism in many, if not all of the neurobiological systems discussed (Hammock & Young, 2006; Baron-Cohen, 2003). The biodiversity underlying these dichotomies should be interrogated from the perspective of comparative psychology and biology.

Table 4

Species Whose Social Inclinations can be Meaningfully Compared

Monogamous vs. Nonmonogamous	Group Adapted vs. Solitary	Domesticated vs. Wild
Prairie Voles (Microtus ochrogaster)  vs. Montane Voles (Microtus montanus)	Spotted Hyenas (Crocutta crocutta) vs. Striped Hyenas (Hyaena hyaena)	Domesticated Dogs (Canis lupus familiaris) vs. Wolves (Canis lupus)
Marten (family Martes) vs. Agouti (family Dasyprocta)	Lions (Panthera leo) vs. Tigers (Panthera tigris)	Domesticated Silver Fox vs. Wild Red Fox (Vulpes vulpes)
California deer mouse (Peromyscus californicus) vs. white-footed mouse (Peromyscus leucopus)	Pigtail macaque (Macaca nemestrina) vs Bonnet macaque (Macaca radiata)	Domesticated Goat (Capra aegagrus hircus) vs. Wild Goat (Capra aegagrus)
Marmoset (family Callitrichidae) vs. Rhesus macaque (Macaca mulatta)	Chimpanzees (Pan troglodytes) vs. Orangutans (Pongo pygmaeus)	Humans (Homo sapiens sapiens) vs. Chimps (Pan troglodytes)
Pine Voles (Microtus pinetorum)  vs. Meadow Voles (Microtus pennsylvanicus)	Ringtailed lemurs (Lemur catta) vs.  Mongoose lemurs (Eulemur mongoz)	Chicken (Gallus gallus) vs. Quail (family Galliformes)

An important question remains: Are the neurobiological mechanisms found in solitary and nonmonogamous mammals sufficient to capture the nuanced social impairments featured in the autism diagnosis? Because of the various, genetic and environmental, etiological contributions to autism (Cantor, 2009) it is clear that only a fraction of what is known as autism could be accurately modeled by cognitive specializations for solitary living in other mammals. The modern, nosological entity of autism is a mixture of phenotypes with separate causes lumped together by clinicians, and a large proportion of it may represent disease that cannot be reliably compared to naturally occurring phenotypes in animals. Based on the paucity of basic research and the absence of consensus in the literature, the present line of research necessitates further critical examination, as well as questioning of the methodology and even the structuring assumptions. Ultimately, understanding ASD will probably require synthesis across several different models, which together should offer complementary and convergent conclusions.

This model, unlike most animal models, does not detail how to alter or program a laboratory animal to mimic aspects of autism. The pronouncements here have not made considerations for immediate application but are much more general and expository. Normally diseases with discrete, recognized causes such as Rett syndrome, Down syndrome and fragile X, are best amenable to animal modeling and immediately suggest treatment options. Highly polygenic disorders that also involve phenotypic plasticity, and de novo mutations, such as autism, are more difficult to model and the models are more difficult to assess. The utility of animal models for autism is commonly assessed using three criteria: (i) face validity (resemblance to human symptoms); (ii) construct validity (similarity to the underlying causes of the disease); and, (iii) predictive validity (expected similar responses to treatments). It is currently not possible to meaningfully assess the validity or value of the present model.

Not only could the study of solitary mammals affect the study of autism, but research in autism could also help to elucidate phenomena in social neuroscience and social psychology. Traits associated with autism, aside from those listed in Tables 1 & 2, should be investigated in a variety of solitary mammals, including: joint attention, pretend play, facial expressiveness, communicative intent, empathy, the mirror neuron system, fusiform recognition areas, and other social cortical areas. Also, this research should have implications for understanding other disorders marked by alterations in related social pathways such as borderline personality disorder, insecure attachment disorder, psychopathy and William’s syndrome. Robert Plomin, author of the leading textbook, Behavioral Genetics (2008), writes: “[We predict that] when genes are found for common disorders such as mild mental retardation or learning disabilities, the same genes will be associated with variation throughout the normal distribution of intelligence, including the high end of the distribution (Plomin et al., 2006).” Could something similar be true throughout the normal distribution of sociality, including social deficits, ASDs and other disorders of bonding, attachment and empathy?

Convergent evolution is pervasive, and the similarities between autism and solitary animals may extend beyond superficial resemblances. An article by Reser (2011) reviews etiological and comparative evidence supporting the hypothesis that some genes associated with the autism spectrum were naturally selected and represent the adaptive benefits of being cognitively suited for solitary foraging. People on the autism spectrum are conceptualized here as potentially ecologically competent. The article suggests that upon independence from their mothers, young individuals on the autism spectrum may have been psychologically predisposed toward a different life-history strategy, common among mammals and even some primates, to hunt and gather primarily on their own. This may have resulted from periodic or geographic disruptions in the efficacy of group foraging in the ancestral past, or from reduced adaptive value of sociocultural information sharing. The resulting evolutionary pressures may have driven the selection of genes that created social processing deficits making their bearers resistant to the transference of units of cultural information (memes). Many of the behavioral and cognitive tendencies that autistic individuals exhibit are viewed as adaptations that would have complemented a solitary lifestyle. Table 5 presents some of these tendencies, their implications for modern individuals and their implications for prehistoric, solitary foragers. The article emphasizes that individuals on the autism spectrum may have only been partially solitary, that natural selection may have only favored subclinical autistic traits and that the most severe cases of autism may be due to assortative mating.

Perhaps components of the autism spectrum can be understood in terms of behavioral ecology and evolutionary medicine, but this does not necessarily mean that autism is an ecological anachronism. Several scientists and many autism advocacy groups promote the idea that autism has compensatory advantages even in modern society (Grandin & Panek 2013; Baron Cohen, 2006). Individuals on the autism spectrum have been shown to exhibit extremely high levels of achievement in systemizing domains, such as mathematics, physics, and computer science (Baron-Cohen et al., 1999) and this is referred to as the “autism advantage” in popular autism advocacy.

Table 5

Behavioral Inclinations in Autism, Then and Now

Trait or Symptom of Autism		Psychological  Consequences		Implications for Moderns	Implications for Solitary Foragers
High systemizing ability	A tendency to systematically explore the laws governing nonsocial processes (Baron Cohen, 2003; 2006)		Eccentric or narrow but substantial knowledge and skills (Treffert, 2000)		An impetus guiding the acquisition of food procurement techniques
Obsessive, repetitious tendencies	Perseveration in behavior and thought (Piven, 2000)		Repetitious play and need for sameness (Kelly et al., 2008 )		Order, structure and autonomous self-regulation
Gaze aversion and absence of shared eye contact	Minimal eye contact and diminished attention to the faces of others (Piven, 2000)		Unfortunate social hurdle (Hutt & Ounsted, 1966)		Instinctually prepared not to challenge or provoke conspecifics
Low oxytocin and vasopressin activity	Reduced social interest, learning and expressiveness (Green et al., 2001)		Unfortunately hindered social cognition (Hollander et al., 2003)		Programmed for a socially impoverished environment
Anomalies in anterior cingulate cortex, orbito and medial frontal cortex Amygdala hyperactivity	Reduced social learning, (Adolphs, 2001) Potentiation of innate and conditioned fears (Dapretto 2006)		Hindered social cognition, imitation, and empathy (Dapretto et al., 2006) Excessive anxiety and withdrawal from social world (Baron Cohen et al., 2000)		Decreased reliance on others Healthy caution, and fear of unfamiliar conspecifics

 

The contemporary, postgenomic age allows molecular methods that were practically inconceivable before genome sequencing was possible. The emerging field of “evolutionary cognitive genetics” makes it clear that there can now be confluence and integration between fields such as brain genomics, human population genetics, and molecular anthropology. The methodology of this field may be applicable here. In order to use modern methods to study the present relationships it might be helpful to: A) perform large-scale comparisons of genes across several strategically selected species in a search for social dimorphisms or social genes with highly elevated rates of evolution in mammals or primates; B) determine if the alleles for these genes are associated with specific social phenotypes using in vitro and in vivo lab studies; and C) subject the candidate genes to polymorphism and association studies in humans.

The analytical tools that social neuroscientists use to study social capacity in other vertebrates can, with appropriate caution, be used to study social capability in humans. Other species have found myriad ways to reduce social contact for ecological purposes, and understanding how this is accomplished may provide insight into prosocial pharmacotherapeutics or even gene therapy for autism. How can the present comparative, neuroethological approach help with autism? In this author’s opinion, the way it can help the most is through comparative neurobiology. It will be interesting to see if neuroanatomical receptor distribution patterns of oxytocin, vasopression, endogenous opioids, prolactin, serotonin and dopamine in the brains of solitary mammals resembles those observed in autism. If there are significant resemblances, it will be important for scientists to compare the distributions patterns of these receptors in different animals to help determine which areas in the autism brain feature a paucity of receptor expression, so that these specific areas can be targeted. It may be possible to test drugs and even behavioral interventions in solitary or nonmonogamous animals to determine if these have the capacity to reverse social interaction deficits. The model may allow an alternate vantage point into the autistic brain, which can only be studied in limited ways because of technical limitations and ethical concerns.