What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: The critical role of early developmental events on prefrontal function

The present review surveys a broad range of findings on the functions of the rodent prefrontal cortex (PFC) in the context of the known pathophysiology of attention-deficit/hyperactivity disorder (ADHD). An overview of clinical findings concludes that dysfunction of the right PFC plays a critical role in ADHD and that a number of early developmental factors conspire to increase the risk of the disorder. Rodent studies are described which go far in explaining how the core processes which are deficient in ADHD are mediated by the PFC and that the mesocortical dopamine (DA) system plays a central role in modulating these functions. These studies also demonstrate a surprising degree of cerebral lateralization of prefrontal function in the rat. Importantly, the PFC is highly vulnerable to a wide variety of early developmental insults, which parallel the known risk factors for ADHD. It is suggested that the regulation of physiological and behavioral arousal is a fundamental role of the PFC, upon which many “higher” prefrontal functions are dependent or at least influenced. These right hemispheric arousal systems, of which the mesocortical DA system is a component, are greatly affected by early adverse events, both peri- and post-natally. Abnormal development, particularly of the right PFC and its DAergic afferents, is suggested to contribute directly to the core deficits of ADHD through dysregulation of the right frontostriatal system

Use of Cognitive Strategies in Rats: the Role of Estradiol and its Interaction with Dopamine

Accumulating evidence suggests a role for estrogen in the use of a particular cognitive strategy when solving a maze task. In order to confirm the role of estrogen in this phenomenon, ovariectomized (OVX) female rats receiving either high (~ 90 pg/ml) or low (~ 32 pg/ml) circulating levels of 17β-estradiol benzoate (E2) performed a plus maze task for a reward. Consistent with previous research, OVX rats receiving low levels of E2 utilized a striatum-mediated response strategy while OVX rats administered high levels of E2 employed a hippocampus-mediated place strategy. Furthermore, following a systemic injection of a moderate dose of either a dopamine D1 (SKF 83566, 0.1 mg/kg IP) or D2 (raclopride, 0.5 mg/kg IP) receptor antagonist, low E2 rats were seen to use the opposite strategy and exercise a hippocampus-mediated place strategy in order to obtain the reward. At the same doses, high E2 rats did not change from using a place strategy. At a lower dose, these drugs shifted high E2 rats such that they showed an equal propensity for either strategy; this was not observed in low E2 rats. These results corroborate previous findings that E2 plays a significant role in the use of either a response or place strategy when solving a maze for a reward. In addition, the shift in strategy after dopamine receptor blockade implies the importance of central dopamine function in selecting a cognitive strategy to solve such tasks. It is suggested that estrogen alters cognitive strategy not only by improving hippocampal function, but also by altering dopamine-regulated striatal function

Prenatal Immune Challenge Induces Developmental Changes in the Morphology of Pyramidal Neurons of the Prefrontal Cortex and Hippocampus in Rats

Background -- The neural mechanisms by which maternal infections increase the risk for schizophrenia are poorly understood; however, animal models using maternal administration of immune activators suggest a role for cytokine imbalance in maternal/fetal compartments. As cytokines can potentially affect multiple aspects of neuronal development and the neuropathology of schizophrenia is believed to involve subtle temporo-limbic neurodevelopmental alterations, we investigated morphological development of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus in rats that were prenatally challenged with the immune activator lipopolysaccharide (LPS). Methods -- Pregnant Sprague-Dawley rat dams were administered with LPS (100μg/kg, at E15 and E16) or saline. The brains of offspring were processed for Golgi-Cox staining at postnatal days (PD) 10, 35 and 56. Dendritic length, branching, spine density and structure were quantified using Neurolucida software. Results -- At all ages, dendritic arbor was significantly reduced in mPFC and CA1 neurons of LPS-treated animals. Dendritic length was significantly reduced in the mPFC neurons of LPS group at PD10 and 35 but returned to control values at PD60. Opposite pattern was observed in CA1 region of LPS animals (normal values at PD10 and 35, but a reduction at PD60). LPS treatment significantly altered the structure of CA1 dendritic spines at PD10. Spine density was found to be significantly lower only in layer V mPFC of PD60 LPS rats. Conclusion -- The study provides the first evidence that prenatal exposure to an immunogen dynamically affects spatio-temporal development of mPFC and hippocampal neurons that can potentially lead to aberrant neuronal connectivity and functions of these structures

Deficits in latent inhibition induced by estradiol replacement are ameliorated by haloperidol treatment

There are sex differences in the symptomatology of schizophrenia, and in the response to antipsychotic treatments. One hallmark symptom of schizophrenia is a deficit in selective attention. Selective attention can be measured using a latent inhibition (LI) paradigm in humans; LI can be measured in rodents, and is used as an animal model of the selective attention deficits observed in schizophrenia. In the current experiments LI was used to clarify whether selective attention differs between male rats and ovariectomized (OVX) female rats receiving different estradiol (E2) replacement regimens. An additional aim was to determine whether haloperidol’s (HAL) facilitation of LI is enhanced by E2. Males and OVX female rats were trained in a conditioned emotional response LI paradigm. Females received no E2 replacement, a chronic low dose of E2 via silastic capsule, or a high phasic dose of E2 via silastic capsule accompanied by E2 (10 µg/kg subcutaneous (SC)) injections every 4th day. Actual plasma levels of E2 were determined using an enzyme linked immunosorbent assay. Rats were also administered a vehicle treatment, a 0.05 mg/kg, or a 0.1 mg/kg IP injection of HAL. Males and OVX females that did not receive E2 replacement both exhibited LI, but LI was not observed in the low and high E2 replacement groups. HAL restored LI at a lower dose in the females receiving high E2 replacement compared to females receiving low E2 replacement, indicating that E2 replacement facilitates HAL in restoring LI

17β-estradiol locally increases phasic dopamine release in the dorsal striatum

Studies using in vivo microdialysis have shown that 17β-estradiol (E2) increases dopamine (DA) transmission in the dorsal striatum. Both systemic administration of E2 and local infusion into the dorsal striatum rapidly enhance amphetamine-induced DA release. However, it is not known to what degree these effects reflect tonic and/or phasic DA release. It was hypothesized that E2 acts directly within the DS to rapidly increase phasic DA transmission. In urethane-anaesthetized (1.5 mL/kg) female rats, we used fast-scan cyclic voltammetry to study the effects of E2 on phasic, electrically-evoked release of DA in the dorsal striatum. Rats were ovariectomized and implanted with a silastic tube containing 5% E2 in cholesterol, previously shown to mimic low physiological serum concentrations of ∼ 20–25 pg/ml. DA release was evoked every 1 min by delivering biphasic electrical stimulation in the substantia nigra. Local infusions of E2 (244.8 pg/μl) into the dorsal striatum increased the amplitude of the electrically evoked DA transients. Behaviorally significant stimuli and events trigger phasic release of DA. The present findings predict that E2 would boost such signaling in behaving subjects

Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum

The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90â 100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapidâ sampling microdialysis (1 sample/min) and highâ performance liquid chromatographyâ tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of nonâ dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5â s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5â s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.Varying the rate of i.v. cocaine delivery between 5 and 90 s determines the drug’s effects on brain and behaviour. We show that injecting cocaine between 5 and 90 s in rats alters the rates of rise of cocaine and dopamine in the dorsal striatum, without significantly changing peak concentrations. Faster injections also increase locomotor behaviour earlier than slower injections. Thus, beyond achieved dose, differences in the rates of rise of cocaine and dopamine can determine outcome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/1/ejn13941-sup-0002-reviewer-Comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/2/ejn13941.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/3/ejn13941-sup-0001-FigS1-S3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151808/4/ejn13941_am.pd

Late style and speaking out: J A Symonds's In the Key of Blue

This article examines In the Key of Blue (1893)—an essay collection by John Addington Symonds—as a case study in queer public utterance during the early 1890s. Viewed through the critical lens of late style, as theorised by Edward Said, the evolution of this project, from compilation through to reader reception, reveals Symonds's determination to “speak out” on the subject of homosexuality. Paradoxically, In the Key of Blue was thus a timely and untimely work: it belonged to a brief period of increased visibility and expressiveness when dealing with male same-sex desire, spearheaded by a younger generation of Decadent writers, but it also cut against the grain of nineteenth-century social taboo and legal repression. Symonds's essay collection brought together new and previously unpublished work with examples of his writing for the periodical press. These new combinations, appearing together for the first time, served to facilitate new readings and new inferences, bringing homosexual themes to the fore. This article traces the dialogic structure of In the Key of Blue , its strategies for articulating homosexual desire, and examines the response of reviewers, from the hostile to celebratory