Predator stress is lastingly anxiogenic. Phosphorylation of CREB to pCREB (phosphorylated cyclic AMP response element binding protein) is increased after predator stress in fear circuitry, including in the right lateral column of the PAG (periaqueductal gray). Predator stress also potentiates right but not left CeA-PAG (central amygdala-PAG) transmission up to 12 days after stress. The present study explored the functional significance of pCREB changes by increasing CREB expression in non-predator stressed rats through viral vectoring, and assessing the behavioral, electrophysiological and pCREB expression changes in comparison with handled and predator stressed controls. Increasing CREB expression in right PAG was anxiogenic in the elevated plus maze, had no effect on risk assessment, and increased acoustic startle response while delaying startle habituation. Potentiation of the right but not left CeA-PAG pathway was also observed. pCREB expression was slightly elevated in the right lateral column of the PAG, while the dorsal and ventral columns were not affected. The findings of this study suggest that by increasing CREB and pCREB in the right lateral PAG, it is possible to produce rats that exhibit behavioral, brain, and molecular changes that closely resemble those seen in predator stressed rats.

Robert Adamec

Olivier Berton

Waleed Abdul Razek

Viral Vector Induction of CREB Expression in the Periaqueductal Gray Induces a Predator Stress-Like Pattern of Changes in pCREB Expression, Neuroplasticity, and Anxiety in Rodents

T. A. Lovick

The Periaqueductal Gray (PAG)

Previous studies have shown that a particular site in the periaqueductal gray (PAG), the rostrolateral PAG, influences the motivation drive to forage or hunt. To have a deeper understanding on the putative paths involved in the decision-making process between foraging, hunting, and other behavioral responses, in the present investigation, we carried out a systematic analysis of the neural inputs to the rostrolateral PAG (rlPAG), using Fluorogold as a retrograde tracer. According to the present findings, the rlPAG appears to be importantly driven by medial prefrontal cortical areas involved in controlling attention-related and decision-making processes. Moreover, the rlPAG also receives a wealth of information from different amygdalar, hypothalamic, and brainstem sites related to feeding, drinking, or hunting behavioral responses. Therefore, this unique combination of afferent connections puts the rlPAG in a privileged position to influence the motivation drive to choose whether hunting and foraging would be the most appropriate adaptive responses.

Sandra Regina Mota-Ortiz

Marcia Harumi Sukikara

Luciano Freitas Felicio

Newton Sabino Canteras

Afferent Connections to the Rostrolateral Part of the Periaqueductal Gray: A Critical Region Influencing the Motivation Drive to Hunt and Forage

Data from studies with humans have suggested that abnormalities of midbrain structures, including the periaqueductal gray matter (PAG), could be involved in the neurobiology of panic disorder (PD). The electrical stimulation of the PAG in neurosurgical patients induces panic-like symptoms and the effect of drugs that are effective in the treatment of PD in the simulation of public speaking model of anxiety is in agreement with data from animal models of PD. Structural neuroimaging studies have shown increases in gray matter volume of midbrain and pons of PD patients. There is also evidence of lower serotonin transporter and receptor binding, and increases of metabolism in the midbrain of PD patients. Nevertheless, these midbrain abnormalities can not be considered as specific findings, since neuroimaging data indicate that PD patients have abnormalities in other brain structures that process fear and anxiety.

Cristina Marta Del-Ben

Frederico Guilherme Graeff

Panic Disorder: Is the PAG Involved?

Chronic morphine administration shifts delta-opioid receptors (DORs) from the cytoplasm to the plasma membrane. Given that microinjection of morphine into the PAG produces antinociception, it is hypothesized that the movement of DORs to the membrane will allow antinociception to the DOR agonist deltorphin II as a way to compensate for morphine tolerance. Tolerance was induced by twice daily injections of morphine (5, 10, or 20 mg/kg, subcutaneous) for 3.5 days. Microinjection of deltorphin into the vPAG 6 hours after the last morphine injection produced a mild antinociception that did not vary in a consistent manner across morphine pretreatment doses or nociceptive tests. In contrast, deltorphin caused a decrease in activity in morphine tolerant rats that was associated with lying in the cage. The decrease in activity and change in behavior indicate that chronic morphine administration alters DORs in the vPAG. However, activation of these receptors does not appear to compensate for the decrease in antinociception caused by morphine tolerance.

Michael M. Morgan

Michelle D. Ashley

Susan L. Ingram

MacDonald J. Christie

Behavioral Consequences of Delta-Opioid Receptor Activation in the Periaqueductal Gray of Morphine Tolerant Rats

Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray (PAG) and its descending projections to the rostral ventromedial medulla (RVM) and spinal cord dorsal horn, as a primary anatomical pathway mediating opioid-based analgesia. Since these initial studies, the PAG-RVM-spinal cord pathway has been characterized anatomically and physiologically in a wide range of vertebrate species. Remarkably, the majority of these studies were conducted exclusively in males with the implicit assumption that the anatomy and physiology of this circuit were the same in females; however, this is not the case. It is well established that morphine administration produces greater antinociception in males compared to females. Recent studies indicate that the PAG-RVM pathway contributes to the sexually dimorphic actions of morphine. This manuscript will review our anatomical, physiological, and behavioral data identifying sex differences in the PAG-RVM pathway, focusing on its role in pain modulation and morphine analgesia.

Dayna R. Loyd

Anne Z. Murphy

The Role of the Periaqueductal Gray in the Modulation of Pain in Males and Females: Are the Anatomy and Physiology Really that Different?

Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1) receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG), a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful stimuli increases endocannabinoid (eCB) levels in the PAG, and local administration of CB1 agonists or drugs that facilitate eCB-mediated neurotransmission produces antinociceptive and antiaversive effects. To investigate if these drugs would also interfere in animal models that are sensitive to anxiolytic drugs, we verified the responses to intra-PAG injection of CB1 agonists in rats submitted to the elevated plus-maze, the Vogel punished licking test, or contextual aversive conditioning model. The drugs induced anxiolytic-like effects in all tests. The same was observed with the transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine and with cannabidiol, a nonpsychotomimetic phytocannabinoid that produces anxiolytic-like effects after systemic administration in humans and laboratory animals. These results, therefore, suggest that the PAG could be an important site for the antiaversive effects of cannabinoids.

F. A. Moreira

D. C. Aguiar

A. C. Campos

S. F. Lisboa

A. L. Terzian

L. B. Resstel

F. S. Guimarães

Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

Cyclical changes in production of neuroactive steroids during the oestrous cycle induce significant changes in 
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</svg> receptor expression in female rats. In the periaqueductal grey (PAG) matter, upregulation of <svg     style="vertical-align:-3.56265pt;width:44.762501px;" id="M2" height="16.6625" version="1.1" viewBox="0 0 44.762501 16.6625" width="44.762501"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> GAB<svg     style="vertical-align:-3.27605pt;width:20.7125px;" id="M3" height="15.5125" version="1.1" viewBox="0 0 20.7125 15.5125" width="20.7125"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.363)"><use xlink:href="#x41"/></g>

			<g transform="matrix(.012,-0,0,-.012,11.813,15.45)"><use xlink:href="#x41"/></g>

		
	
</svg> receptors occurs as progesterone levels fall during late dioestrus (LD) or during withdrawal from an exogenous progesterone dosing regime. The new receptors are likely to be extrasynaptically located on the GABAergic interneurone population and to mediate tonic currents. Electrophysiological studies showed that when <svg     style="vertical-align:-3.56265pt;width:44.762501px;" id="M4" height="16.6625" version="1.1" viewBox="0 0 44.762501 16.6625" width="44.762501"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FC"/></g><g transform="matrix(.017,-0,0,-.017,9.718,12.162)"><use xlink:href="#x34"/></g><g transform="matrix(.017,-0,0,-.017,17.877,12.162)"><use xlink:href="#x1D6FD"/></g><g transform="matrix(.017,-0,0,-.017,27.753,12.162)"><use xlink:href="#x31"/></g><g transform="matrix(.017,-0,0,-.017,35.913,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg> GAB<svg     style="vertical-align:-3.27605pt;width:20.7125px;" id="M5" height="15.5125" version="1.1" viewBox="0 0 20.7125 15.5125" width="20.7125"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.363)"><use xlink:href="#x41"/></g>

			<g transform="matrix(.012,-0,0,-.012,11.813,15.45)"><use xlink:href="#x41"/></g>

		
	
</svg> receptor expression was increased, the excitability of the output neurones in the PAG increased, due to a decrease in the level of ongoing inhibitory tone from the GABAergic interneurones. The functional consequences in terms of nociceptive processing were investigated in conscious rats. Baseline tail flick latencies were similar in all rats. However, acute exposure to mild vibration stress evoked hyperalgesia in rats in LD and after progesterone withdrawal, in line with the upregulation of <svg     style="vertical-align:-3.56265pt;width:44.762501px;" id="M6" height="16.6625" version="1.1" viewBox="0 0 44.762501 16.6625" width="44.762501"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> receptor expression.

A. J. Devall

Progesterone Withdrawal-Evoked Plasticity of Neural Function in the Female Periaqueductal Grey 
Matter

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<p><em>Neural Plasticity</em> is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.</p>


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Neural Plasticity is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.

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Neural Plasticity

The Periaqueductal Gray (PAG)

The Periaqueductal Gray (PAG)

Articles

Viral Vector Induction of CREB Expression in the Periaqueductal Gray Induces a Predator Stress-Like Pattern of Changes in pCREB Expression, Neuroplasticity, and Anxiety in Rodents

The Periaqueductal Gray (PAG)

Afferent Connections to the Rostrolateral Part of the Periaqueductal Gray: A Critical Region Influencing the Motivation Drive to Hunt and Forage

Panic Disorder: Is the PAG Involved?

Behavioral Consequences of Delta-Opioid Receptor Activation in the Periaqueductal Gray of Morphine Tolerant Rats

The Role of the Periaqueductal Gray in the Modulation of Pain in Males and Females: Are the Anatomy and Physiology Really that Different?

Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

Progesterone Withdrawal-Evoked Plasticity of Neural Function in the Female Periaqueductal Grey Matter