Within the last decade several genes have been identified as candidate risk genes for developmental dyslexia. Recent research using animal models and embryonic RNA interference (RNAi) has shown that a subset of the candidate dyslexia risk genes—DYX1C1, ROBO1, DCDC2, KIAA0319—regulate critical parameters of neocortical development, such as neuronal migration. For example, embryonic disruption of the rodent homolog of DYX1C1 disrupts neuronal migration and produces deficits in rapid auditory processing (RAP) and working memory—phenotypes that have been reported to be associated with developmental dyslexia. In the current study we used a modified prepulse inhibition paradigm to assess acoustic discrimination abilities of male Wistar rats following in utero RNA interference targeting Kiaa0319. We also assessed spatial learning and working memory using a Morris water maze (MWM) and a radial arm water maze. We found that embryonic interference with this gene resulted in disrupted migration of neocortical neurons leading to formation of heterotopia in white matter, and to formation of hippocampal dysplasia in a subset of animals. These animals displayed deficits in processing complex acoustic stimuli, and those with hippocampal malformations exhibited impaired spatial learning abilities. No significant impairment in working memory was detected in the Kiaa0319 RNAi treated animals. Taken together, these results suggest that Kiaa0319 plays a role in neuronal migration during embryonic development, and that early interference with this gene results in an array of behavioral deficits including impairments in rapid auditory processing and simple spatial learning.

Disruptions in the development of the neocortex are associated with cognitive deficits in humans and other mammals. Several genes contribute to neocortical development, and research into the behavioral phenotype associated with specific gene manipulations is advancing rapidly. Findings include evidence that variants in the human gene DYX1C1 may be associated with an increased risk of developmental dyslexia. Concurrent research has shown that the rat homolog for this gene modulates critical parameters of early cortical development, including neuronal migration. Moreover, recent studies have shown auditory processing and spatial learning deficits in rats following in utero transfection of an RNA interference (RNAi) vector of the rat homolog Dyx1c1 gene. The current study examined the effects of in utero RNAi of Dyx1c1 on working memory performance in Sprague-Dawley rats. This task was chosen based on the evidence of short-term memory deficits in dyslexic populations, as well as more recent evidence of an association between memory deficits and DYX1C1 anomalies in humans. Working memory performance was assessed using a novel match-to-place radial water maze task that allows the evaluation of memory for a single brief (∼4-10 seconds) swim to a new goal location each day. A 10-min retention interval was used, followed by a test trial. Histology revealed migrational abnormalities and laminar disruption in Dyx1c1 RNAi-treated rats. Dyx1c1 RNAi-treated rats exhibited a subtle, but significant and persistent impairment in working memory as compared to Shams. These results provide further support for the role of Dyx1c1 in neuronal migration and working memory.

Recent studies show that dense dopamine (DA) innervation from the ventral tegmental area (VTA) to the olfactory tubercle (OT) may play an important role in processing multisensory information pertaining to arousal and reward, yet little is known about DA regulation in the OT. This is mainly due to the anatomical limitations of conventional methods to determine DA dynamics in small heterogeneous OT subregions located in the ventral most part of the brain. Additionally, there is increasing awareness that anteromedial and anterolateral subregions of the OT have distinct functional roles in natural and psychostimulant drug reinforcement as well as regulating other types of behavioral responses such as aversion. Here, we compared extracellular DA regulation (release and clearance) in three subregions (anteromedial, anterolateral, and posterior) of the OT of urethane-anesthetized rats using in vivo fast-scan cyclic voltammetry following electrical stimulation of VTA dopaminergic cell bodies. The neurochemical, anatomical, and pharmacological evidence confirmed that the major electrically evoked catecholamine in the OT was DA across both its anteroposterior and mediolateral extent. While both D2 autoreceptors and DA transporters play important roles in regulating evoked DA in OT subregions, DA in the anterolateral OT was regulated less by the D2 receptors when compared to other OT subregions. Comparing previous data of other DA rich ventral striatum regions, the slow DA clearance across the OT subregions may lead to a high extracellular DA concentration and contribute towards volume transmission. These differences in DA regulation in the terminals of OT subregions and other limbic structures will help us understand the neural regulatory mechanisms of DA in the OT, which may elucidate its distinct functional contribution in the ventral striatum towards mediating aversion, reward and addiction processes.

Dyslexia is a complex neurodevelopmental disorder characterized by impaired reading ability despite normal intellect, and is associated with specific difficulties in phonological and rapid auditory processing, visual attention, and working memory. Genetic variants in DCDC2 have been associated with dyslexia, impairments in phonological processing, and in short term/working memory. The purpose of this study was to determine whether sensory and behavioral impairments can result directly from mutation of the Dcdc2 gene in mice. Several behavioral tasks, including a modified pre-pulse inhibition paradigm (to examine auditory processing), a 4/8 radial arm maze (to assess/dissociate working versus reference memory), and rotarod (to examine sensorimotor ability and motor learning) were used to assess the effects of Dcdc2 mutation. Behavioral results revealed deficits in rapid auditory processing, working memory, and reference memory in Dcdc2del2/del2 mice as compared to matched wild types. Current findings parallel clinical research linking genetic variants of DCDC2 with specific impairments of phonological processing and memory ability.

Methamphetamine (METH) is a potent psychostimulant that exerts many of its physiological and psychomotor effects by increasing extracellular dopamine (DA) concentrations in limbic brain regions. While several studies have focused on how potent, neurotoxic doses of METH augment or attenuate DA transmission, the acute effects of lower and behaviorally activating doses of METH on modulating DA regulation (release and clearance) through DA D2 autoreceptors and transporters remain to be elucidated. In this study, we investigated how systemic administration of escalating, subneurotoxic doses of METH (0.5–5 mg/kg, IP) alter extracellular DA regulation in the nucleus accumbens (NAc), in both anesthetized and awake‐behaving rats through the use of in vivo fast‐scan cyclic voltammetry. Pharmacological, electrochemical, and behavioral evidence show that lower doses (≤2.0 mg/kg, IP) of METH enhance extracellular phasic DA concentrations and locomotion as well as stereotypies. In contrast, higher doses (≥5.0 mg/kg) further increase both phasic and baseline DA concentrations and stereotypies but decrease horizontal locomotion. Importantly, our results suggest that acute METH‐induced enhancement of extracellular DA concentrations dose dependently activates D2 autoreceptors. Therefore, these different METH dose‐dependent effects on mesolimbic DA transmission may distinctly impact METH‐induced behavioral changes. This study provides valuable insights regarding how low METH doses alter DA transmission and paves the way for future clinical studies on the reinforcing effects of METH.

The current study investigated the behavioral and neuroanatomical effects of embryonic knockdown of the candidate dyslexia susceptibility gene (CDSG) homolog Dyx1c1 through RNA interference (RNAi) in rats. Specifically, we examined long-term effects on visual attention abilities in male rats, in addition to assessing rapid and complex auditory processing abilities in male and, for the first time, female rats. Our results replicated prior evidence of complex acoustic processing deficits in Dyx1c1 male rats and revealed new evidence of comparable deficits in Dyx1c1 female rats. Moreover, we found new evidence that knocking down Dyx1c1 produced orthogonal impairments in visual attention in the male subgroup. Stereological analyses of male brains from prior RNAi studies revealed that, despite consistent visible evidence of disruptions of neuronal migration (i.e., heterotopia), knockdown of Dyx1c1 did not significantly alter the cortical volume, hippocampal volume, or midsagittal area of the corpus callosum (measured in a separate cohort of like-treated Dyx1c1 male rats). Dyx1c1 transfection did, however, lead to significant changes in medial geniculate nucleus (MGN) anatomy, with a significant shift to smaller MGN neurons in Dyx1c1-transfected animals. Combined results provide important information about the impact of Dyx1c1 on behavioral functions that parallel domains known to be affected in language-impaired populations as well as information about widespread changes to the brain following early disruption of this CDSG.

Hypoxia-ischemia (HI; reduction in blood/oxygen supply) is common in infants with serious birth complications, such as prolonged labor and cord prolapse, as well as in infants born prematurely (<37 weeks gestational age; GA). Most often, HI can lead to brain injury in the form of cortical and subcortical damage, as well as later cognitive/behavioral deficits. A common domain of impairment is working memory, which can be associated with heightened incidence of developmental disorders. To further characterize these clinical issues, the current investigation describes data from a rodent model of HI induced on postnatal (P)7, an age comparable to a term (GA 36–38) human. Specifically, we sought to assess working memory using an eight-arm radial water maze paradigm. Study 1 used a modified version of the paradigm, which requires a step-wise change in spatial memory via progressively more difficult tasks, as well as multiple daily trials for extra learning opportunity. Results were surprising and revealed a small HI deficit only for the final and most difficult condition, when a delay before test trial was introduced. Study 2 again used the modified radial arm maze, but presented the most difficult condition from the start, and only one daily test trial. Here, results were expected and revealed a robust and consistent HI deficit across all weeks. Combined results indicate that male HI rats can learn a difficult spatial working memory task if it is presented in a graded multi-trial format, but performance is poor and does not appear to remediate if the task is presented with high initial memory demand. Male HI rats in both studies displayed impulsive characteristics throughout testing evidenced as reduced choice latencies despite more errors. This aspect of behavioral results is consistent with impulsiveness as a core symptom of ADHD—a diagnosis common in children with HI insult. Overall findings suggest that task specific behavioral modifications are crucial to accommodating memory deficits in children suffering from cognitive impairments following neonatal HI.

Developmental dyslexia is a disorder characterized by a specific deficit in reading despite adequate overall intelligence and educational resources. The neurological substrate underlying these significant behavioral impairments is not known. Studies of post mortem brain tissue from male and female dyslexic individuals revealed focal disruptions of neuronal migration concentrated in the left hemisphere, along with aberrant symmetry of the right and left the planum temporale, and changes in cell size distribution within the medial geniculate nucleus of the thalamus (Galaburda et al., 1985; Humphreys et al., 1990). More recent neuroimaging studies have identified several changes in the brains of dyslexic individuals, including regional changes in gray matter, changes in white matter, and changes in patterns of functional activation. In a further effort to elucidate the etiology of dyslexia, epidemiological and genetic studies have identified several candidate dyslexia susceptibility genes. Some recent work has investigated associations between some of these genetic variants and structural changes in the brain. Variants of one candidate dyslexia susceptibility gene, KIAA0319, have been linked to morphological changes in the cerebellum and functional activational changes in the superior temporal sulcus (Jamadar et al., 2011; Pinel et al., 2012). Animal models have been used to create a knockdown of Kiaa0319 (the rodent homolog of the human gene) via in utero RNA interference in order to study the gene’s effects on brain development and behavior. Studies using this animal model have demonstrated that knocking down the gene leads to focal disruptions of neuronal migration in the form of ectopias and heterotopias, similar to those observed in the brains of human dyslexics. However, further changes to the structure of the brain have not been studied following this genetic disruption. The current study sought to determine the effects of embryonic Kiaa0319 knockdown on volume of the cortex and hippocampus, as well as midsagittal area of the corpus callosum in male rats. Results demonstrate that Kiaa0319 knockdown did not change the volume of the cortex or hippocampus, but did result in a significant reduction in the midsagittal area of the corpus callosum. Taken in the context of previous reports of behavioral deficits following Kiaa0319 knockdown (Szalkowski et al., 2012), and reports that reductions of corpus callosum size are related to processing deficits in humans (Paul et al., 2011), these results suggest that Kiaa0319 has a specific involvement in neural systems important for temporal processing.