INTRODUCTION
Psychological factors such as stressful events induce a coordinated set
of behavioural and physiological changes (McEwen, 2000). In the short
term, physiological adjustments are important adaptive responses that
maintain homeostasis and ensure survival (Sterling, 2012). The
physiological responses to stress are mainly characterized by
alterations in the autonomic nervous system and cardiovascular system,
increases in plasma catecholamine levels and activation of the
hypothalamic-pituitary-adrenal (HPA) axis (Herman et al., 2016; Joels &
Baram, 2009). Autonomic responses include increases in both blood
pressure (BP) and heart rate (HR) (Campeau & Watson, 1997; R. A.
Dampney, Horiuchi, & McDowall, 2008), a drop in tail skin temperature
as a consequence of sympathetically mediated vasoconstriction in skin
beds (Blessing & Seaman, 2003; Nakamura, 2015; Vianna & Carrive, 2005)
and baroreflex activity modulation (Crestani, 2016; R. A. L. Dampney,
2017).
Studies using image analysis techniques and Fos protein measurement have
demonstrated that stressful stimuli activate neurons in the insular
cortex (IC) (Ahn et al., 2015; Imbe, Kimura, Donishi, & Kaneoke, 2014;
Uematsu, Kitamura, Iwatsuki, Uneyama, & Tsurugizawa, 2015). In
addition, nonselective synaptic blockade in the IC generated by local
microinjection of CoCl2 decreased both the increased blood pressure and
tachycardia evoked by restraint stress (Alves, Crestani, & Correa,
2010). Moreover, the inhibition of local IC neurotransmission by CoCl2
attenuated freezing and increased the mean arterial pressure and heart
rate in the groups that received CoCl2 either immediately after
conditioning or 10 min before re-exposure to the aversive context but
not in the group that received CoCl2 before the conditioning session.
Regarding the HPA axis response, cortical regions such as the prefrontal
cortex are related to the control of the HPA axis (Ekstrand, Hellsten,
& Tingstrom, 2008; Gjerstad, Lightman, & Spiga, 2018; Neigh, Owens,
Taylor, & Nemeroff, 2010) and participate in negative feedback via
intermediate synapses in the PVN (Herman, McKlveen, Solomon,
Carvalho-Netto, & Myers, 2012; Ulrich-Lai & Herman, 2009). In limbic
areas such as the hippocampus and prefrontal cortex, glutamatergic
neurotransmission plays an inhibitory role in the HPA axis (Diorio,
Viau, & Meaney, 1993; Figueiredo, Bodie, Tauchi, Dolgas, & Herman,
2003; Ulrich-Lai & Herman, 2009). IC seems to be related to the
regulation of cortisol in women with depression (Ottowitz et al., 2004).
The presence of glutamatergic terminals has been demonstrated in the IC
(Dori, Dinopoulos, Cavanagh, & Parnavelas, 1992). In addition,
microinjection of glutamate into the IC caused cardiovascular responses
(Butcher & Cechetto, 1995; Ranjbar, Hatam, & Nasimi, 2015; Ruggiero,
Mraovitch, Granata, Anwar, & Reis, 1987), showing that IC glutamatergic
neurotransmission participates in the modulation of cardiovascular
activity. Glutamatergic neurotransmission via NMDA receptors in the IC
also has a facilitatory influence on baroreflex activity (Alves,
Crestani, Resstel, & Correa, 2009), suggesting that the control of
stress-evoked cardiovascular changes might be mediated by modulation of
this cardiovascular reflex mechanism. Thus, in the present study, we
tested the hypothesis that cardiovascular, neuroendocrine and autonomic
responses to an acute session of restraint stress are mediated by
glutamatergic neurotransmission in the IC.