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BackgroundPsychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cyclic adenosine monophosphate signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect.MethodsA variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current, while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance.ResultsImmunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased HCN channel current, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation.ConclusionsThese findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses.

Objective: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. Method: Monkeys performed a working memory task after administration of a wide range of MPH or ATM doses. The optimal doses were challenged with the alpha[subscript 2]-adrenoceptor antagonist, idazoxan, or the D[subscript 1] dopamine receptor antagonist, SCH23390 (SCH). In a parallel physiology study, neurons were recorded from the dorsolateral PFC of a monkey performing a working memory task. ATM, SCH, or the alpha[subscript 2] antagonist, yohimbine, were applied to the neurons by iontophoresis. Results: MPH and ATM generally produced inverted-U dose-response curves, with improvement occurring at moderate doses, but not at higher doses. The beneficial effects of these drugs were blocked by idazoxan or SCH. At the cellular level, ATM produced an inverted-U dose-response effect on memory-related firing, enhancing firing for preferred directions (increasing "signals") and decreasing firing for the nonpreferred directions (decreasing "noise"). The increase in persistent firing for the preferred direction was blocked by yohimbine, whereas the suppression of firing for the nonpreferred directions was blocked by SCH. Conclusions: Optimal doses of MPH or ATM improved PFC cognitive function in monkeys. These enhancing effects appeared to involve indirect stimulation of alpha[subscript 2] adrenoceptors and D[subscript 1] dopamine receptors in the PFC. These receptor actions likely contribute to their therapeutic effects in the treatment of attention-deficit/hyperactivity disorder. (Contains 5 figures.)

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction (1-4). The PFC guides behaviour and thought using working memory (5), which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation (6). This fragile process is highly dependent on the neurochemical environment (7). For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels (8,9). It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits., Our society is rapidly ageing, with the number of seniors in the United States expected to double by 2050 (United States census, http://www.census.gov/population/www/pop-profile/elderpop.html). At the same time, the information age [...]

A study of the effects attention-deficit/hyperactivity disorder drugs methylphenidate (MPH) and atomexetine (ATM) on monkeys' prefrontal cortex (PFC) function is presented. The monkeys' PFC cognitive function was enhanced when treated with optimal doses of MPH and ATM. The indirect stimulation of alpha adrenoreceptors and D1 dopamine receptors has contributed to that effect.

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits. [ABSTRACT FROM AUTHOR]

The article presents a study on the effects of the attention-deficit/hyperactivity disorder (ADHD) treatments, methylphenidate (MPH) and atomoxetine (ATM) on the prefrontal cortex (PFC) of monkeys. It says that 18 monkeys, ages ranging from 6 to 29 years old, performed a manual version of the spatial working memory (WM) task to examine performance. It notes that the moderate doses of MPH and ATM improved spatial WM in monkeys which are likely to contribute in the treatment of patients with ADHD.

Many surgeons are faced with inoperable or only partially operable brain lesions, such as tumors. Even when surgery is feasible, patient outcome is greatly affected by blood loss or infection. This has led many physicians toward non- or minimally-invasive surgery, which demands specialized toolkits. Focused ultrasound has great potential for assisting in such procedures due to its ability to focus a few cm away from the surface of the transducer. In a prior study, we developed a focused ultrasound prototype that could fit within a BrainPath trocar, specifically made for minimally invasive brain surgery. Here, we present the design and fabrication of a second prototype that reduces size, is MR-compatible, and has electronic steering capabilities.