Graham V. Williams

A role for inhibition in shaping the temporal flow of information in prefrontal cortex

The prefrontal cortex is important in guiding or inhibiting future responses, which requires the temporal integration of events and which provides continuity to the thought process. No cellular mechanism has been proposed to explain how the mental representation of a response or idea is linked to the next. Using simultaneous recordings in monkeys, we revealed inhibitory interactions between neurons active at different time points relative to the cue presentation, delay interval and response period of a working memory task. These findings suggest an important role of inhibition in the cerebral cortex—controlling the timing of neuronal activities during cognitive operations and thereby shaping the temporal flow of information.

Dopaminergic regulation of cerebral cortical microcirculation.

Functional variations in cerebral cortical activity are accompanied by local changes in blood flow, but the mechanisms underlying this physiological coupling are not well understood. Here we report that dopamine, a neurotransmitter normally associated with neuromodulatory actions, may directly affect local cortical blood flow. Using light and electron-microscopic immunocytochemistry, we show that dopaminergic axons innervate the intraparenchymal microvessels. We also provide evidence in an in vitro slice preparation that dopamine produces vasomotor responses in the cortical vasculature. These anatomical and physiological observations reveal a previously unknown source of regulation of the microvasculature by dopamine. The findings may be relevant to the mechanisms underlying changes in blood flow observed in circulatory and neuropsychiatric disorders.

The cerebral cortex: a case for a common site of action of antipsychotics

Recent evidence from studies of receptor occupancy and regulation in post-mortem brains of patients with neuropsychiatric disorders and in non-human primates is providing new leads in the ongoing quest to understand the pathophysiology and causes of schizophrenia and to develop more effective methods of treatment. These studies suggest that the cerebral cortex may harbour the elusive common sites of action of antipsychotic medications and indicate that chronic treatment with these drugs differentially regulates both families of dopamine receptors in this structure. Upregulation of the cortical dopamine D2 receptors is accompanied by a downregulation of the D1 sites. Balancing the opposing actions of dopamine D1 and D2 receptor regulation may hold the key to optimal drug therapy and to understanding the pathophysiology of schizophrenia. In this article, Michael Lidow, Graham Williams and Patricia Goldman-Rakic review the evidence supporting the cerebral cortex as a pivotal site for these mechanisms underlying the action of antipsychotics.

Immediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors

BACKGROUND Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic α7 receptor could improve spatial working memory in nonhuman primates. METHODS Beginning with an estimated dose range from rodent studies, the dose of the α7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg-.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg-1.0 μg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout. RESULTS Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg. CONCLUSIONS These findings demonstrate that extremely low doses of a nicotinic α7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the α7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend.

A chamber and artificial dura method for long-term optical imaging in the monkey

Optical imaging over extended periods of time in non-human primates presents serious challenges because the dura mater must be removed to expose the cortical surface. We present a novel nylon imaging chamber with a transparent artificial dura implant, which allows repeated, long-term optical recordings from the cortex. The cylinder of the chamber is inserted into a cranial trephination and held in place with a minimum of screws and acrylic cement. A round patch of artificial dura with a perpendicular wall protects the cortical surface and slows re-growth of dural tissue within the chamber. A cap, manufactured from the same material as the cylinder, is screwed into the chamber and seals it completely. Over a period of 1-4 months, the chamber required a minimum of maintenance and stayed infection-free without local antibiotic application. We repeatedly performed optical imaging in the same animal with the advantages of shortened preparation time. To permit precise alignment and comparison of maps obtained from different imaging sessions, we developed a program that calculated a 2-dimensional spatial transformation between maps of different magnifications, translations, and distortions. We suggest that these methods provide a practical solution to long-term optical imaging in the anesthetized or alert monkey. The exclusive use of non-metallic materials offers the benefit of a lighter and more compact implant, and the possibility to perform MRI scans after chamber implantation.

Reduction of Brain Kynurenic Acid Improves Cognitive Function

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia

Current treatments for psychiatric disorders were developed with the aim of providing symptomatic relief rather than reversing underlying abnormalities in neuroplasticity or neurodevelopment that might contribute to psychiatric disorders. This review considers the possibility that psychiatric treatments might be developed that target neuroplasticity deficits or that manipulate neuroplasticity in novel ways. These treatments might not provide direct symptomatic relief. However, they might complement or enhance current pharmacotherapies and psychotherapies aimed at the prevention and treatment of psychiatric disorders. In considering neuroplasticity as a target for the treatment of psychiatric disorders, we build on exciting new findings in the areas of anxiety disorders, mood disorders, and schizophrenia.

Glycine transporter inhibition reverses ketamine-induced working memory deficits

Glycine transporter inhibitors have recently been reported to improve symptoms in patients with schizophrenia. Here we used acute ketamine in the nonhuman primate to test the effectiveness of the novel glycine transporter inhibitor, PF-3463275, in a model of cognitive dysfunction relevant to schizophrenia. PF-3463275 (0.01–0.17 mg/kg; subcutaneously) or a vehicle was given before the administration of ketamine (median dose of 1.0 mg/kg intramuscularly) or placebo (saline). Ketamine induced hallucinatory-like behaviors that were not reversed by PF-3463275. In contrast, all doses of PF-3463275 alleviated the deficit in spatial working memory induced by ketamine. Theses findings build upon those in patients by providing translational support for targeting glycine transporter in adjunctive treatment for cognitive dysfunction in schizophrenia.

Reversal of Ketamine-Induced Working Memory Impairments by the GABAAα2/3 Agonist TPA023

BACKGROUND Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms. METHODS Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection. RESULTS Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamines cognitive-impairing ability but did not influence the behavioral symptoms. CONCLUSIONS Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling.

Molecular dynamics and crystallization behaviour of isopentyl cyanobiphenyl as studied by dielectric relaxation spectroscopy

Isopentyl cyanobiphenyl may be cooled into the supercooled liquid state, forming a glass below 210 K. On heating the glass, the supercooled liquid crystallizes above 245 K. Dielectric relaxation spectroscopy (DRS) has been used in the frequency range 10−1 to 105 Hz to study (i) the reorientational motions of the molecules in the glassy and supercooled liquid states and (ii) the kinetics of crystallization. A primary (α) relaxation process is observed whose line-shape is discussed in terms of the Kohlrausch–Williams–Watts function and component relaxation processes. The temperature dependence of the dielectric relaxation time is found to conform with the Vogel–Fulcher–Tamman equation. The crystallization kinetics, as determined from DRS measurements on heating the supercooled liquid, are shown to follow the Avrami equation but the experimental values of the Avrami exponent are far smaller than the theoretical value for the sporadic growth of spherulites.