Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC
Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic acid (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, or latent inhibition deficits reported in Poly IC-treated rats but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).
"Animals tested for locomotor activity received three phases of testing: Baseline with no treatment; Saline with saline-only injection; and drug challenge with one of three drugs (see   ). At young ages, there was no significant main effect of diet; there was a significant diet × interval interaction (F(11,3466) = 2.39, p < 0.01). "
[Show abstract][Hide abstract] ABSTRACT: Manganese overexposure (MnOE) can be neurotoxic. In humans this can occur through occupational exposure, air or water contamination, well water, soy milk, and some baby formulas. In children MnOE has been associated with cognitive and behavioral deficits. The effects of MnOE may be modified by factors such as iron status. We hypothesized that developmental MnOE would be exacerbated by iron deficiency. A diet with a 90% decrease in iron (FeD) was given to gravid female rats starting on embryonic day 15 and continued through postnatal day (P)28. Mn (100 mg/kg) or vehicle (VEH) was administered by gavage every other day from P4-28. Metal transporters and receptors (divalent metal transporter-1 (DMT1), transferrin (Tf), transferrin receptor (TfR), and zip8 (zrt8)) were quantified in brain at P28. These markers were increased but the changes were specific: MnOE increased TfR and decreased Tf in hippocampus, whereas FeD increased TfR in neostriatum and increased TfR and DMT1 in the hippocampus, and the combination increased TfR in neostriatum (zip8 was unaffected). Identically treated animals were tested behaviorally at P29 or P60. The combination of FeD+MnOE increased head dips in an elevated zero-maze, reversed deficits in sucrose preference induced by MnOE alone, and increased spontaneous locomotion in an open-field. Rats were also evaluated for changes in locomotor activity after challenge with (±)-fenfluramine (FEN, a 5-HT agonist: 5 mg/kg), MK-801 (MK801, an NMDA antagonist: 0.2 mg/kg), or (+)amphetamine (AMPH, a dopamine agonist: 1 mg/kg). Compared with VEH animals, MnOE animals were more hyperactive after fenfluramine, amphetamine, or MK-801, regardless of FeD exposure. The results indicate persistent effects of developmental MnOE on brain and behavior but few interactions with dietary iron deficiency.
"The present results using Long Evans rats are consistent with previous reports that MIA during pregnancy does not alter classical fear conditioning in the adult male offspring of either Wistar (Zuckerman and Weiner, 2005) or Sprague Dawley rat strains (Vorhees et al., 2012; Yee et al., 2012). The previous studies assessed freezing to auditory cues and context previously paired with footshock (Vorhees et al., 2012; Yee et al., 2012) and suppression of licking to an auditory cue previously paired with footshock in a conditioned emotional response paradigm (Zuckerman and Weiner, 2005). We report robust freezing to the cue and context on day one during conditioning and day 2 during the initial phase of the first extinction session, which provides a measure of conditioning recall 24 h after training (Figure 2). "
[Show abstract][Hide abstract] ABSTRACT: Maternal immune activation (MIA) during pregnancy is an environmental risk factor for psychiatric illnesses such as schizophrenia and autism in the offspring. Hence, changes in an array of behaviors, including behavioral flexibility, consistent with altered functioning of cortico-limbic circuits have been reported in rodent models of MIA. Surprisingly, previous studies have not examined the effect of MIA on the extinction of fear conditioning which depends on cortico-limbic circuits. Thus, we tested the effects of treating pregnant Long Evans rats with the viral mimetic polyI:C (gestational day 15; 4 mg/kg; i.v.) on fear conditioning and extinction in the male offspring using two different tasks. In the first experiment, we observed no effect of polyI:C treatment on the acquisition or extinction of a classically conditioned fear memory in a non-discriminative auditory cue paradigm. However, polyI:C-treated offspring did increase contextual freezing during the recall of fear extinction in this non-discriminative paradigm. The second experiment utilized a recently developed task to explicitly test the ability of rats to discriminate among cues signifying fear, reward, and safety; a task that requires behavioral flexibility. To our surprise, polyI:C-treated rats acquired the task in a manner similar to saline-treated rats. However, upon subsequent extinction training, they showed significantly faster extinction of the freezing response to the fear cue. In contrast, during the extinction recall test, polyI:C-treated offspring showed enhanced freezing behavior before and after presentation of the fear cue, suggesting an impairment in their ability to regulate fear behavior. These behavioral results are integrated into the literature suggesting impairments in cortico-limbic brain function in the offspring of rats treated with polyI:C during pregnancy.
[Show abstract][Hide abstract] ABSTRACT: Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.
Neurotoxicology and Teratology 08/2012; 36. DOI:10.1016/j.ntt.2012.07.007 · 2.76 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.