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Genetic Vasopressin Deficiency Facilitates Performance of a Lateralized Reaction-Time Task: Altered Attention and Motor Processes

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Genetic Vasopressin Deficiency Facilitates Performance of a Lateralized Reaction-Time Task: Altered Attention and Motor Processes 1066 • The Journal of Neuroscience, February 1, 2003 • 23(3):1066–1071 Genetic Vasopressin Deficiency Facilitates Performance of a Lateralized Reaction-Time Task: Altered Attention and Motor Processes J. David Jentsch Department of Psychology, University of California, Los Angeles, California 90095-1563 Brattleboro rats are a variety of the outbred Long–Evans strain that possess a single nucleotide deletion in the second exon of the arginine vasopressin gene, resulting in the synthesis of an altered protein that does not enter the normal secretory pathway. Rats heterozygous (di/ϩ) for the deletion have a partial vasopressin deficiency and exhibit a variety of behavioral and neurochemical alterations compared with normal wild-type Long–Evans rats, which provide evidence for a CNS function for vasopressin. Here, we examined the acquisition and performance of a test of visuospatial attention by di/ϩ Brattleboro rats and their wild-type Long–Evans control counterparts. Surprisingly, di/ϩ rats exhibited superior performance of the task compared with wild-type controls; performance differences included greater accuracy of detection of visual target stimuli, faster overall reaction times, and fewer trial omissions. Di/ϩ rats also exhibited more approaches to the reinforcer receptacle at nonreinforcement times. These results indicate that alterations of vasopressin signaling result in a clear cognitive phenotype, including faster motor initiations and superior choice accuracy in a test of visual attention. Key words: attention; vasopressin; Brattleboro rat; cognition; autism; schizophrenia Introduction alternation (i.e., working memory) (Colombo et al., 1992), and Although little is known about the biochemical pharmacology of prepulse inhibition (i.e., sensorimotor gating) (Feifel and Priebe, vasopressinergic synapses in the brain, substantial evidence sup- 2001), with di/ϩ rats generally showing a partial phenotype. It ports the notion that this nonapeptide plays a role in CNS func- has been suggested that these data indicate that vasopressin plays tion. Receptors for vasopressin (the V1A receptor in particular) a role in regulating a number of psychological domains. are expressed in a number of forebrain structures (Barberis and The behavioral impairments in Brattleboro rats have been Tribollet, 1996), and pharmacologic manipulations of the vaso- interpreted as evidence that these mutant rats may serve not only pressin system can produce alterations of cognitive and social as a model for vasopressin deficiency but also for autism (Insel et behaviors in rats (Insel et al., 1999). Although the effects of vaso- al., 1999) and/or schizophrenia (Feifel and Priebe, 2001). Central pressin analogs on cognition are inconsistent, overall (Strupp to both of these disorders are alterations of visual attention; pa- and Levitsky, 1985), the evolving evidence seems to suggest that tients with schizophrenia exhibit deficits of sustained attention vasopressin regulates various aspects of cognition, including (Nuechterlein, 1977) as well as impairments of executive aspects learning, memory, and/or attention. of attention (e.g., attention shifting) (Pantelis et al., 1997). Inter- Evidence for a role for vasopressin in cognition comes from estingly, patients with autism show enhancements of low-level studies of the Brattleboro rat. Brattleboro rats are a variety of the visual processing, including visual search, feature discrimination, Long–Evans strain that possess a single nucleotide deletion in the and superior focused versus divided attention (Plaisted et al., second exon of the arginine vasopressin gene. The resulting frame 1999; O’Riordan and Plaisted, 2001; O’Riordan et al., 2001). shift causes synthesis of an altered protein that does not enter the These facilitations of low-level visual processing and attention normal secretory pathway. Rats homozygous (di/di) for the de- appear to be in tandem with impairments of executive aspects of letion have no detectable circulating vasopressin concentration, attention (Allen and Courchesne, 2001). exhibit a variety of behavioral and neurochemical alterations We sought to evaluate the acquisition and performance by compared with normal wild-type Long–Evans rats, and have di- di/ϩ Brattleboro and wild-type rats of a lateralized reaction-time ϩ abetes insipidus. Heterozygous (di/ ) Brattleboro rats are par- task that measures visuospatial attention and motor initiation; tially vasopressin-deficient. A number of studies have indicated homozygous animals were not studied because of the concern that di/di Brattleboro rats exhibit deficits of social recognition that the consequent diabetes insipidus may complicate compar- (i.e., affiliative behavior) (Engelmann and Landgraf, 1994), con- isons of food-motivated performance. In the task used, animals ditioned fear (i.e., affective learning) (Stoehr et al., 1993), delayed initiate the presentation of a visual target stimulus at one of two possible spatial locations and then make a response toward the Received Sept. 3, 2002; revised Oct. 29, 2002; accepted Nov. 13, 2002. location of the target. Therefore, this task requires sustained and This work was supported by the University of California. I thank Alexander Arguello for artistic contributions, J. divided attention. We also evaluated response times to gauge Kristin Martin for technical assistance, and Luigi Anzivino for useful discussions. motor-initiation speeds in both groups. Here, we report the re- Correspondence should be addressed to Dr. J. David Jentsch, Department of Psychology, University of California at Los Angeles, P.O. Box 951563, Los Angeles, CA 90095-1563. E-mail: [email protected]. sults of these investigations; partial vasopressin deficiency pro- Copyright © 2003 Society for Neuroscience 0270-6474/03/231066-06$15.00/0 duces superior accuracy of detection and faster response times. Jentsch • Attention in Vasopressin-Deficient Rats J. Neurosci., February 1, 2003 • 23(3):1066–1071 • 1067 Materials and Methods Subjects. Sixty-day-old male rats [heterozygous (di/ϩ) Brattleboro or wild-type Long–Evans rats] were purchased from Harlan (Indianapolis, IN) and were housed in genotype-specific triads on a 14.5/9.5 hr light/ dark cycle, with lights on at 6:30 A.M.; all behavioral testing was con- ducted during the light phase. The subjects were initially deprived of food to 90% of their free-feeding weights and subsequently fed 15 gm of rat chow per day in their home cages (1 hr after testing). Water was contin- uously available except during the testing period. This feeding schedule was sufficient to allow all subjects to gain ϳ5–10% body weight per week. The experimental protocols used were consistent with the National In- stitutes of Health’s Guide for the Care and Use of Laboratory Animals and were approved by the Chancellor’s Animal Research Committee at the University of California at Los Angeles. Behavioral testing apparatus. The design of the operant chambers is based on that described by Carli et al. (1983). Standard extra-tall alumi- num and Plexiglas operant chambers equipped with a light bulb and infrared beam pellet-delivery magazine on one side and a curved panel with five nose-poke apertures on the opposite side (Med Associates, E. Fairfield, VT) were used. The boxes were housed inside of a sound- attenuating cubicle; background white noise was broadcast, and the en- vironment was illuminated with a house light (a light diffuser that was located outside of the operant chamber but within the cubicle). Pretraining. All of the rats first received free reinforcer (45 mg Bioserv dustless precision; Bio-Serv, Frenchtown, NJ) pellets in their home cages for 3 consecutive days before commencing training. Subsequently, all rats were trained in a single session in which the house light was contin- uously illuminated and single pellets were delivered into an illuminated magazine on a fixed-time 20 sec schedule over a 45 min period. One day after magazine training, the rats were trained to make a sus- tained nose-poke at the center aperture in three consecutive daily ses- sions. On the first day, the session began with illumination of the house light; a variable-duration nose-poke of 10, 200, 400, or 600 msec was required in the illuminated center aperture to trigger a pellet to be dis- pensed within the head-entry magazine on the back wall (the nose-poke duration requirements were varied randomly from trial to trial). When the rat successfully responded for the duration of the hold period, the head-entry magazine was illuminated and a pellet was dispensed. After the rat retrieved the pellet, the magazine light was extinguished, and 3 sec Figure 1. Schematic figure displaying the general task contingency. The trial onset is sig- later the center aperture was illuminated to signal the initiation of an- naled by illumination of the central nose-poke aperture. A response of variable duration at the other trial. The session terminated after 60 min passed or the rat earned centralaperturethenresultsintargetdeliveryinoneofthelateralapertures.Aresponsetoward 100 pellets, whichever occurred first. On the second and third days, the the target is reinforced; an incorrect choice or failure to respond (omission) is punished with a 3 procedure was identical except that the rat was required to sustain 10, sec time-out. 200, 500, or 700 msec nose-pokes on the second day and 200, 500, 700, or 1000 msec nose-pokes on the third day. tation or the limited hold period, the animal received a 3 sec time-out in Acquisition of the lateralized reaction-time task. After being trained to darkness and an omission was recorded. In both cases, the time-out make the sustained nose-poke, rats began daily testing on the lateralized period was immediately followed by illumination of the house light dif- reaction-time task (the general task contingency is shown in Fig. 1); in the fuser and by the illumination of the center aperture 3 sec later. first four sessions, a target stimulus of fixed duration was presented for all An additional contingency was in place to discourage premature re- trials in a session (which terminated after 60 min or 128 trials, whichever sponses.
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