CO2 exposure as translational cross-species experimental model for panic.

The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.

The brain acid-base homeostasis and serotonin: A perspective on the use of carbon dioxide as human and rodent experimental model of panic.

Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed.

Localization and behaviors in null mice suggest that ASIC1 and ASIC2 modulate responses to aversive stimuli.

Acid-sensing ion channels (ASICs) generate H(+) -gated Na(+) currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1(-/-) mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

First Report of Maize streak virus Field Infection of Sugarcane in South Africa.

Prior to the introduction of highly resistant sugarcane varieties, Sugarcane streak virus (SSV) caused serious sugar yield losses in southern Africa. Recently, sugarcane plants with streak symptoms have been identified across South Africa. Unlike the characteristic fine stippling and streaking of SSV, the symptoms resembled the broader, elongated chlorotic lesions commonly observed in wild grasses infected with the related Maize streak virus (MSV). Importantly, these symptoms have been reported on a newly released South African sugarcane cultivar, N44 (resistant to SSV). Following a first report from southern KwaZulu-Natal, South Africa in February 2006, a survey in May 2007 identified numerous plants with identical symptoms in fields of cvs. N44, N27, and N36 across the entire South African sugarcane-growing region. Between 0.04 and 1.6% of the plants in infected fields had streak symptoms. Wild grass species with similar streaking symptoms were observed adjacent to one of these fields. Potted stalks collected from infected N44 plants germinated in a glasshouse exhibited streak symptoms within 10 days. Virus genomes were isolated and sequenced from a symptomatic N44 and Urochloa plantaginea plants collected from one of the surveyed fields (1). Phylogenetic analysis determined that while viruses from both plants closely resembled the South African maize-adapted MSV strain, MSV-A4 (>98.5% genome-wide sequence identity), they were only very distantly related to SSV (~65% identity; MSV-Sasri_S: EU152254; MSV-Sasri_G: EU152255). To our knowledge, this is the first confirmed report of maize-adapted MSV variants in sugarcane. In the 1980s, "MSV strains" were serologically identified in sugarcane plants exhibiting streak symptoms in Reunion and Mauritius, but these were not genetically characterized (2,3). There have been no subsequent reports on the impact of such MSV infections on sugarcane cultivation on these islands. Also, at least five MSV strains have now been described, only one of which, MSV-A, causes significant disease in maize and it is unknown which strain was responsible for sugarcane diseases on these islands in the 1980s (2,3). MSV-A infections could have serious implications for the South African sugar industry. Besides yield losses in infected plants due to stunting and reduced photosynthesis, the virus could be considerably more difficult to control than it is in maize because sugarcane is vegetatively propagated and individual plants remain within fields for years rather than months. Moreover, there is a large MSV-A reservoir in maize and other grasses everywhere sugarcane is grown in southern Africa. References: (1) B. E. Owor et al. J Virol. Methods 140:100, 2007. (2) M. S. Pinner and P. G. Markham. J. Gen. Virol. 71:1635, 1990. (3) M. S. Pinner et al. Plant Pathol. 37:74, 1998.

Role of the M1 receptor in regulating circadian rhythms.

Cholinergic stimuli are potent regulators of the circadian clock in the hypothalamic suprachiasmatic nucleus (SCN). Using a brain slice model, we have found that the SCN clock is subject to muscarinic regulation, a sensitivity expressed only during the night of the clock's 24-h cycle. Pharmacological and signal transduction characteristics are compatible with a response mediated by an M1-like receptor. Molecular manipulation of muscarinic receptors will provide important insights as to the receptor subtype(s) regulating circadian rhythms.

Differential cAMP gating of glutamatergic signaling regulates long-term state changes in the suprachiasmatic circadian clock.

We investigated a role for cAMP/protein kinase A (PKA) in light/glutamate (GLU)-stimulated state changes of the mammalian circadian clock in the suprachiasmatic nucleus (SCN). Nocturnal GLU treatment elevated [cAMP]; however, agonists of cAMP/PKA did not mimic the effects of light/GLU. Coincident activation of cAMP/PKA enhanced GLU-stimulated state changes in early night but blocked light/GLU-induced state changes in the late night, whereas inhibition of cAMP/PKA reversed these effects. These responses are distinct from those mediated by mitogen-activated protein kinase (MAPK). MAPK inhibitors attenuated both GLU-induced state changes. Although GLU induced mPer1 mRNA in both early and late night, inhibition of PKA blocked this event only in early night, suggesting that cellular mechanisms regulating mPer1 are gated by the suprachiasmatic circadian clock. These data support a diametric gating role for cAMP/PKA in light/GLU-induced SCN state changes: cAMP/PKA promotes the effects of light/GLU in early night, but opposes them in late night.

Pituitary adenylyl cyclase-activating peptide: a pivotal modulator of glutamatergic regulation of the suprachiasmatic circadian clock.

The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus organizes behavioral rhythms, such as the sleep-wake cycle, on a near 24-h time base and synchronizes them to environmental day and night. Light information is transmitted to the SCN by direct retinal projections via the retinohypothalamic tract (RHT). Both glutamate (Glu) and pituitary adenylyl cyclase-activating peptide (PACAP) are localized within the RHT. Whereas Glu is an established mediator of light entrainment, the role of PACAP is unknown. To understand the functional significance of this colocalization, we assessed the effects of nocturnal Glu and PACAP on phasing of the circadian rhythm of neuronal firing in slices of rat SCN. When coadministered, PACAP blocked the phase advance normally induced by Glu during late night. Surprisingly, blocking PACAP neurotransmission, with either PACAP6-38, a specific PACAP receptor antagonist, or anti-PACAP antibodies, augmented the Glu-induced phase advance. Blocking PACAP in vivo also potentiated the light-induced phase advance of the rhythm of hamster wheel-running activity. Conversely, PACAP enhanced the Glu-induced delay in the early night, whereas PACAP6-38 inhibited it. These results reveal that PACAP is a significant component of the Glu-mediated light-entrainment pathway. When Glu activates the system, PACAP receptor-mediated processes can provide gain control that generates graded phase shifts. The relative strengths of the Glu and PACAP signals together may encode the amplitude of adaptive circadian behavioral responses to the natural range of intensities of nocturnal light.

A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock.

Circadian clocks are complex biochemical systems that cycle with a period of approximately 24 hours. They integrate temporal information regarding phasing of the solar cycle, and adjust their phase so as to synchronize an organism's internal state to the local environmental day and night. Nocturnal light is the dominant regulator of this entrainment. In mammals, information about nocturnal light is transmitted by glutamate released from retinal projections to the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Clock resetting requires the activation of ionotropic glutamate receptors, which mediate Ca2+ influx. The response induced by such activation depends on the clock's temporal state: during early night it delays the clock phase, whereas in late night the clock phase is advanced. To investigate this differential response, we sought signalling elements that contribute solely to phase delay. We analysed intracellular calcium-channel ryanodine receptors, which mediate coupled Ca2+ signalling. Depletion of intracellular Ca2+ stores during early night blocked the effects of glutamate. Activators of ryanodine receptors induced phase resetting only in early night; inhibitors selectively blocked delays induced by light and glutamate. These findings implicate the release of intracellular Ca2+ through ryanodine receptors in the light-induced phase delay of the circadian clock restricted to the early night.