Genetic Basis of Separation Anxiety

Infant Separation Responses and Anxiety

When an infant is separated from its mother, its immediate behavioral response is the "separation cry", and consists of repeated vocalizations and diffusely agitated behavior. This initial behavioral response to separation is characteristic of most mammalian species, including humans. Though considered adaptive in some contexts, pathologically increased separation anxiety in children has been associated with earlier onset of adult social phobias and panic disorder. Separation anxiety is also seen far more frequently in children in families in which adults show anxiety disorders. These studies strongly suggest that separation anxiety may be a precursor for adult inherited anxiety disorders.

Rat Pup Ultrasonic Vocalizations (USV) and Anxiety

For infant rats (pups), the immediate vocal response to separation is a high frequency (45 kHz) ultrasonic vocalization (USV). Rat pup USVs consist of short calls in series which can be counted, and the most commonly reported measure is number or rate. For nearly two decades rat pup USV has been used as a model of anxiety, since drugs acting to reduce anxiety (anxiolytics) and antidepressants across a spectrum of neurochemical receptors reduce rates of infant USV. These global effects of anxiolytics suggest that rat pup USV may provide a good animal model for separation anxiety as a generalized precursor to more discrete forms of adult anxiety, such as anxiety disorders.

Development of the Lines of Rats Selectively Bred for Infant USV.

While the infant rat USV model has been useful, what has been missing is an animal model with pathological levels of this infantile trait. This laboratory has produced two lines of rats selectively bred for high and low extremes of USV rates in infancy. Adult High and Low USV Line rats are bred based on their USV rates assessed for 2 minutes as infants isolated away from mother and littermates. The achievement of selective breeding is itself evidence that the USV response to separation is an inherited trait.

In creating the High and Low selectively bred lines our goal was to produce central nervous system differences regulating anxiety. In general, High USV line rats show an "anxious/depressed" phenotype in both behavior and autonomic nervous system regulation to standard laboratory tests. Autonomic nervous system regulation and more limited behavioral information suggest the possibility of an "aggressive" profile in Lows. Thus the selected lines have the potential to be an exceptional research tool with which to model inherited lifelong traits conferring risk for dysregulated responses to stress.

Selected Publications:


Brunelli , S.A. , Nie, R., Whipple, C., Winiger, V., Hofer, M.A., Zimmerberg, B. (2006) The effects of selective breeding on play behavior in juvenile rats. Physiology & Behavior, 87: 527-536.

Brunelli, S.A .  (2005) Development and evolution of hidden regulators: Selective breeding for an infantile phenotype. Developmental Psychobiology, 47:243-52.

Muller, J.M ., Brunelli, S.A ., Moore, H ., Myers, M.M ., Shair, H.N . (2005) Maternally modulated infant separation responses are regulated by D2-family dopamine receptors. Behavioral Neuroscience, 119: 1384-1388.

Bamat N.A., Brunelli , S.A . , Kron, M.M., Schulte, A.R., Zimmerberg, B. (2005) Behavioral effects of toluene in rats selectively bred for infantile vocalization rate. Neurotoxicology and Teratology, 27:883-890.

Zimmerberg, B., Fluty, A., Samuels, M., Brunelli , S.A. , Frye. C.A. (2005) Differences in affective behaviors and hippocampal allopregnanolone levels in adult rats of lines selectively bred for infantile vocalizations. Behavioral Brain Research,159:301-310.

Brunelli , S.A . (2005) Selective breeding for an infant phenotype: Rat pup ultrasonic vocalization (USV). Behavioral Genetics, 35:53-65.

Shair, H.N., Brunelli, S.A ., Hofer, M.A. (2005) Lack of evidence for mu-opioid regulation of a socially mediated separation response. Physiology & Behavior, 83:767-777.

Myers, M.M., Ali, N., Weller, A., Brunelli, S.A ., Tu, A.Y., Hofer, M.A., Shair, H.N. (2004) Brief maternal interaction increases number, duration, amplitude, and bout length of isolation-induced ultrasonic vocalizations in infant rats. Journal of Comparative Psychology, 118: 95-102.

Brunelli , S.A . , Myers, M.M., Asekoff, S.L., Hofer, M.A. (2002) Effects of selective breeding for infant rat ultrasonic vocalization on cardiac responses to isolation. Behavioral Neuroscience, 116, 612-623.

Hofer, M.A., Masmela, J.R., Shair, H.N., Brunelli, S.A . (2001) Developmental effects of selective breeding for an infantile trait: The rat pup ultrasonic isolation call. Developmental Psychobiology, 39: 231-246 .

Brunelli , S.A . , Weller, A., Hofer, M.A. (2001) Selective breeding for infant vocal response: A role for postnatal maternal effects? Developmental Psychobiology, 38:221-228.

Brunelli , S.A . , Masmela, J.R., Shair, H.N., Hofer, M.A. (1998) Effects of biparental rearing on ultrasonic vocalization (USV) responses of rat pups ( Rattus norvegicus ). Journal of Comparative Psychology, 112: 331-343.

Shair, H.N., Masmela, J.R., Brunelli, S.A ., Hofer, M.A. (1997) Potentiation and inhibition of ultrasonic vocalization of rat pups: Regulation by social cues. Developmental Psychobiology, 30: 195-200.

Brunelli , S.A. , Vinocur, D.D., Soo-Hoo D., Hofer, M.A. (1997) Five generations of selective breeding for ultrasonic vocalization (USV) responses in N:NIH strain rats. Developmental Psychobiology, 31: 255-265.

Dichter, G.S., Brunelli, S.A ., Hofer, M.A. (1996) Elevated plus-maze behavior in adult offspring of selectively bred rats. Physiology & Behavior, 60: 299-304.

Brunelli, S.A ., Hofer, M.A. (1996) Development of ultrasonic vocalization responses in genetically heterogeneous National Institute of Health (N:NIH) rats. II. Associations among variables and behaviors. Developmental Psychobiology, 29: 517-528.

Brunelli , S.A . , Keating, C.C., Hamilton , N.A., Hofer, M.A. (1996) Development of ultrasonic vocalization responses in genetically heterogeneous National Institute of Health (N:NIH) rats. I. Influence of age, testing experience and associated factors. Developmental Psychobiology, 29: 507-516.