Abrahams et al., in their landmark study of
the defense reaction (DR), proposed that the
hypothalamic defense area (HDA) was a
longitudinal narrow strip of undifferentiated
gray matter in the lateral hypothalamus (LH).
The region of the undifferentiated gray matter
that yielded the largest cardiovascular
responses was located in the perifornical area
in the LH (PF/ LH). The cardiovascular
components of the DR were never linked to
specific nuclei within the hypothalamus. This
view of the HDA, which originated from studies
in the cat, has been supported by subsequent
studies in rats and baboons. The PF/LH is
ventral and lateral to the hypothalamic region
in which electrical stimulation elicits the
defense reaction in the rabbit and GABA
antagonists evoke the defense response in the
rat.
Recent studies in rats and in cats indicate
that stimulation of the paraventricular nucleus
of the hypothalamus (PVN) elicits increases in
blood pressure and heart rate. Stimulation of
the PVN also leads to an increase in blood flow
to the skeletal muscles and a decrease in blood
flow to the viscera. This cardiovascular
response pattern is similar to the one seen in
the DR. The PVN projects to brain stem and
spinal cord structures that are involved in
cardiovascular regulation, and has an
established role in the regulation of posterior
pituitary gland secretions. These observations
suggest that this nucleus plays an important
role in the integration of endocrine and
autonomic responses to environmental
stressors.
The DR is a protypical integrated
somatic/autonomic response to threatening
environmental stimuli, so it seems reasonable to
hypothesize that the PVN is involved in the
mediation or modulation of the autonomic
components of this response pattern. The present
study was designed to test this hypothesis, by
comparing the cardiorespiratory responses
elicited by PVN stimulation with those that we
have observed in studies of the hypothalamic
defense area (HDA) in the rabbit. More
specifically, we assessed the effects of
electrical stimulation of the PVN upon: 1. Blood
pressure, heart rate, and respiration; 2.
Hindlimb and visceral blood flow; 3. The
neuropharmacological mechanisms that mediate
hindlimb blood flow; and 4. The
depressor/bradycardia response elicited by
aortic nerve stimulation. [...]
Discussion
Cardiorespiralory Response Pattern
Elicited by Electrical Stimulation of the
Paraventricular Nucleus
Electrical stimulation of the PVN of the
rabbit produces a pressor response, tachycardia,
and hyperventilation. A pressor/ tachycardia
response from electrical stimulation of the PVN
bas also been reported for the rat and cat. The
observation that this response pattern is also
evoked by chemical stimulation of the same
region indicates that it is mediated by cell
bodies rather than axons of passage.
The cardiorespiratory response pattern
elicited by PVN stimulation is similar to the
one we observed when we stimulated the HDA in
the rabbit. It is also similar to the one
elicited by electrical stimulation of the HDA in
cats and rats, and by chernical stimulation of
the HDA in rats.
Changes in Hindlimb and Visceral Blood
Flow Evoked by PVN Stimulation
The defense reaction is characterized by an
increase in hindlimb blood flow and a decrease
in blood flow to the viscera. Electrical
stimulation of the PVN was observed, in the
present study, to produce the same pattern of
blood-flow changes. An increase in hindlimb
blood flow from PVN stimulation has also been
observed in the rat.
Another study from this laboratory presented
evidence for a cholinergie skeletal muscle
vasodilation system in the rabbit, and that the
increases in hindlimb blood flow from HDA
stimulation were mediated, at least in part, by
this mechanism. The results of the present study
indicate that an atropine-sensitive cholinergic
mechanisrn can be activated by electrical
stimulation of the PVN. In addition to this
muscarinic cholinergic mechanism, a
beta2-receptor-mediated vasodilation system has
also been postulated to contribute to the
increase in hindlimb blood flow that occurs
during the defense reaction. Our observation
that the skeletal muscle vasodilation that
results from PVN stimulation was attenuated by
the beta2-antagonist ICI 118 551 provides
support for this view. Watkins have suggested
that the beta2-receptor-mediated vasodilation
elicited by electrical stimulation of the
defense area in the midbrain periaqueductal gray
matter in rats is primarily involved in the late
component (after the terrnination of the
electrical stimulation) of the vasodilation
response.
Modulation of the Baroreceptor Reflex by
PVN Stimulation
Electrical stimulation of the AN, which in
the rabbit is exclusively barosensory, elicits a
depressor/bradycardia response pattern that
would be triggered by an increase in blood
pressure. Inhibition of the baroreceptor reflex
is thought to occur during the defense reaction.
Some investigators have reported inhibition of
the cardiomotor component and the vasomotor
component of the reflex, and others report that
the cardiomotor was suppressed but that the
vasomotor component of the reflex was not. PVN
stimulation inhibited the cardiomotor reflex,
but the vasomotor component was not
significantly affected. Similar observations
were made when we used the same experimental
paradigm to assess the effects of HDA
stimulation upon the aortic nerve-elicited
depressor/bradycardia response, though we
observed a small enhancement of the vasomotor
component of the reflex in that study.
Role of the PVN in Mediating or
Modulating the Defense Reaction
The results of the present study provide
evidence that the PVN is involved in the
modulation or mediation of the cardiorespiratory
components of the defense reaction. The exact
role that the PVN plays in the defense reaction
is a matter for speculation. PVN neurons project
to neuroanatomical sites that yield the defense
reaction when stimulated electrically, including
the dorsomedial portion of the posterior
hypothalamus, the dorsal PAG, and the central
nucleus of the amygdala. Also, the fact that the
PVN makes direct projections to brainstem
regions involved in the cardiorespiratory
components of the defense reaction suggests the
possibility that it may not be connected in
series with other structures associated with the
defense reaction.
The PVN may also be a part of an afferent
feedback pathway that modulates the defense
reaction. Activation of chemoreceptors afferents
leads to defense behaviors in decorticate cats,
and the cardiovascular components of the defense
reaction in anesthetized cats. Moreover,
activation of peripheral baroreceptors can
attenuate the behavioral and autonomic
components of defensive responses in cats. As
suggested elsewhere, neuroanatomical and
electrophysiological evidence is consistent with
the view the PVN is a part of the afferent
feedback pathway from buffer nerve afferents to
regions of the amygdala that yield the defense
reaction when stimulated electrically.
The PVN plays an important role in the
integration of the autonomic and endocrine
furictions that subserve behavioral needs in
response to environmental challenges or
stressors. In regard to the defense reaction,
there may be a dissociation between the
autonomic and behavioral components (ie., fight
or flight) of this response pattern at the PVN
so that electrical stimulation of this site
yields the cardiorespiratory components of the
response pattern, but not the behavioral
components; we have not tested the effects of
electrical stimulation of the PVN in conscious
rabbits. Recent findings from other laboratories
provide evidence that the PVN is involved in the
mediation or modulation of the behavioral
components of the defense reaction. Lesions of
the PVN not only block the tachycardia evoked by
footshock stress, but also reduce the behavioral
struggling induced by forced swimming stress.
Furthermore, injections of toxic doses of NMDA
into the PVN have been reported to elicit marked
behavioral excitation, exopthalmos, and
mydriasis. These responses are similar to those
seen in the defense reaction.
In summary, electrical stimulation of the
PVN in rabbits produces hemodynamic and
respiratory changes that are nearly identical to
those associated with the defense reaction.
Heart-rate and blood-pressure increases are
coupled with hyperventilation, decreased blood
flow to the visceral organs, and increased blood
flow to the hindlimbs. The increase in hindlimb
blood flow elicited by PVN stimulation is
mediated by an atropine -sensitive vasodilation
system and the cardiomotor component of the
baroreceptor reflex is inhibited when the PVN is
stimulated. Taken together, these findings
provide evidence that the PVN is involved in the
mediation or modulation of the defense reaction.
The PVN is located in a neuroanatomical
position that would allow it to modulate other
brain structures involved in the defense
reaction, be connected in series or parallel
with one or more of these structures, or
modulate the defense reaction by mediating
feedback from chemoreceptors and baroreceptors.
