This issue covers a broad territory of PAG
function: neuropharmacology, functional organization, and PAG plasticity in adaptive behavior, emotion, anxiety, and the less-studied
plasticity of the PAG function in
females.Interest in the involvement of PAG in defensive behavior has a long history. Thinking about this area was
radically changed by the seminal contributions of Bandler and DePaulis in
defining functional columns arranged in both coronal and saggital planes of the
PAG. Most papers in this section
respect the importance of those functional columns while adding to our
understanding how they might contribute to panic, anxiety, defensive response
to natural threats, as well as aversive learning.Del-Ben and Graeff
in the paper entitled “Panic disorder: Is the PAG involved?” review preclinical as well as human imaging research in the
contribution of PAG dysfunction to
panic anxiety disorder. Others have shown how preclinical models of
posttraumatic stress disorder (PTSD) and using brief exposure to predators
(predator stress) have helped to advance our understanding of the neural
substrates of stress-induced lasting sensitization of rodent anxiety including
potentiation of startle response. Adamec et al. contribution in the paper
entitled “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” extends
initial findings implicating pCREB expression in the lateral column of the PAG in neuroplastic changes in amygdala-PAG communication as mediators of predator stress-enhanced
startle and anxiety. Using viral vector enhancement of CREB expression in the PAG, the authors
provide support for the idea that stress-precipitated increases in pCREB in the
PAG are sufficient to potentiate
central amygdala to PAG neural
transmission, to increase anxiety in the elevated plus maze, and to potentiate startle
response. In a related vein, exposure to stressful stimuli increases endocannabinoid
(eCB) levels in the PAG and local
administration of cannabinoid receptor 1 (CB1) agonists or drugs that
facilitate eCB-mediated neurotransmission produce antinociceptive and
antiaversive effects. Stimulated by these findings, Moreira et al. in “Anti-aversive
effects of cannabinoids: is the periaqueductal gray involved?” explore the anxiolytic potential of PAG injection of CB1 agonists and cannabidiol in a
variety of tests of anxiety as well as in contextual fear conditioning. They
provide evidence that dorsal lateral PAG is a site of antiaversive actions of cannabinoids. Other PAG columnar function (ventrolateral
PAG-VlPAG) in
antinociception is explored by Morgan
et al. in “Behavioral Consequences of Delta Opioid Receptor
Activation in the Periaqueductal Gray of Morphine Tolerant Rats”. It is known that chronic
morphine administration shifts delta-opioid receptors (DOR)
from the cytoplasm to the plasma membrane. Moreover, microinjection of morphine
into the VlPAG produces antinociception. In light of these findings, it was
hypothesized that movement of DORs to the membrane would induce antinociception
to the DOR agonist deltorphin II
as a way to compensate for morphine tolerance. Their findings suggest that
chronic morphine administration alters DORs in the vlPAG with little evidence
of compensation for the decrease in antinociception caused by morphine
tolerance.PAG Function in Females. Until very recently, research on the
PAG along with most other brain areas was conducted almost exclusively
in males with the implicit assumption that the anatomy and physiology were the same in females. Three articles in this issue show
that this is not the case. Not only are there significant differences in
the organization of the PAG between the sexes but the circuitry of the female PAG also exhibits considerable plasticity in response to changes in its hormonal
milieu.Lloyd and Murphy in the paper entitled “The
Role of the Periaqueductal Gray in the Modulation of Pain in Males and Females:
Is the Anatomy and Physiology Really That Different?” show that descending projections from the PAG, which are believed to modulate spinal
processing of nociceptive input, are more numerous in female rats than in
males. Paradoxically morphine, which exerts much of its antinociceptive effects
by activating these projections, excited a much smaller proportion of the
neurones in females compared to males, a finding that may explain the clinical
finding of reduced efficacy of the analgesic effects of morphine in women compared
to men. Lovick and Devall in the paper entitled “The
Role of the Periaqueductal Gray in the Modulation of Pain in Males and Females: Is the Anatomy and Physiology Really That Different?” show how the fall in production of progesterone
during the late dioestrus phase of the oestrous cycle leads to upregulation of
certain subunits of the GABAA receptor in the PAG. One of the functional consequences is a
decrease in ongoing GABAergic tone and an increase in neural excitability
within PAG circuits. These changes
may underlie the increased susceptibility to the development of stress-induced
hyperalgesia that was shown to occur during late dioestrus and may also be
relevant to Lloyd and Murphy's reports of a reduction in morphine's efficacy in
female rats during
dioestrus. Mota-Ortiz et al. in the paper entitled “Afferent Connections
to the Rostrolateral Part of the Periaqueductal Gray: a Critical Region Influencing
the Motivation Drive to Hunt and Forage” examine afferent inputs to the rostrolateral PAG (rlPAG ) in female rats. In nursing females, morphine treatment induces a behavioral “switch” from maternal to foraging behavior which is
mediated via the rostrolateral PAG (rlPAG ). The authors report that the rlPAG receives inputs from medial
prefrontal cortical areas involved in controlling attention-related and
decision-making processes. Other afferents from different amygdalar,
hypothalamic, and brainstem sites provide information to PAG related to feeding, drinking, or hunting
behaviors. It is suggested that this unique combination of afferent connections
positions the rlPAG to influence the decision whether hunting/foraging or other
behaviors would be the most appropriate adaptive response for females,
particularly in the presence of their young.These
papers are by no means exhaustive of the interest and breadth of work in the PAG field. Nevertheless, together they reflect the
rich functional diversity of activities of the PAG.
Moreover, they make apparent the importance of paying attention to sex and particular
columnar areas when studying this fascinating structure, whose activity is of
fundamental importance for survival of the individual in a challenging and
constantly changing environment.