GABAergic mechanisms of anterior and ventromedial hypothalamic nuclei in the expression of freezing in response to a light-conditioned stimulus.

Abstract

The amygdala, dorsal periaqueductal gray (dPAG), and medial hypothalamus have long been recognized to comprise a neural system responsible for the generation and elaboration of unconditioned fear in the brain. This neural substrate is well known to be under tonic inhibitory control exerted by γ-aminobutyric acid (GABA) mechanisms. Some evidence also suggests that these structures integrate conditioned fear. A recent study using the fear-potentiated startle paradigm showed that GABAergic mechanisms in the anterior hypothalamic nucleus (AHN) and dorsomedial part of the ventromedial hypothalamic nucleus (VMHDM) regulate conditioned fear. The present study examined the extent to which GABAergic mechanisms in these brain regions are involved in conditioned fear by measuring freezing in response to a light used as a conditioned stimulus (CS). The GABA A receptor agonist muscimol and the GABA-synthesizing enzyme glutamic acid decarboxylase inhibitor semicarbazide were used as an enhancer and inhibitor of GABA mechanisms, respectively. Muscimol and semicarbazide were injected into the AHN or VMHDM of rats before fear conditioning. Muscimol injections into the AHN and VMHDM significantly reduced conditioned freezing, whereas inhibition of GABA transmission increased this conditioned response in the AHN. The present study further supports the hypothesis that GABAergic mechanisms in the AHN and VMHDM exert inhibitory control on the neural substrates of conditioned fear in the hypothalamus.

Ventromedial hypothalamic neurons control a defensive emotion state

“…In addition, we find that optogenetic activation of SF1 + neurons in VMHdm/c can indeed serve as an unconditional stimulus (US) for associative learning, in a conditioned place avoidance assay. These data, together with earlier studies of conditioning in VMH ( Colpaert and Wiepkema, 1976 ; Santos et al, 2008 ; Santos and Brandão, 2011 ) and associated hypothalamic nuclei ( Pavesi et al, 2011 ), provide definitive evidence against the view that the hypothalamus is not an emotion center ( Masserman, 1941 ; Wada and Matsuda, 1970 ). Yet this perspective is still common in textbook views of emotion ([ LeDoux and Damasio, 2013 ], in [ Kandel et al, 2013 ]), which place the amygdala as the central ‘orchestrator’ of emotion systems, and the hypothalamus as a motor effector or relay of amygdala output.…”

“…VMHdm/c SF1 + neurons send projections to the BNST, AHN, lateral hypothalamus (LHA), PMd, MeA and dorsal peri-aqueductal gray (dPAG), as well as to other structures (see Figure 1—figure supplement 1 ; Video 9, 10 ) ( Canteras et al, 1994 ). Previous studies have shown that perturbations of some of these targets, including the dPAG or PMd, can influence some defensive behaviors ( Di Scala et al, 1987 ; Di Scala and Sandner, 1989 ; Canteras et al, 1997 ; Blanchard et al, 2003b ; Bittencourt et al, 2005 ; Cezario et al, 2008 ; Pagani and Rosen, 2009 ; Sukikara et al, 2010 ; Pavesi et al, 2011 ; Santos and Brandão, 2011 ; Kincheski et al, 2012 ). However, many of these earlier studies did not exclude a role for stimulation of fibers of passage, and lacked the cellular specificity and spatio-temporal resolution of the methods employed here.…”

Electromagnetic Field and Γ Aminobutyric Acid a Receptors Interaction in the Fear Response

“…Muscimol infusion impaired differential fear responding as the level of freezing to inhibitory conditioned stimulus was indiscriminable from that to excitatory conditioned stimulus (Lee and Choi, 2012). Muscimol injections into the Anterior Hypothalamic Nucleus (AHN) and Ventromedial Nucleus of the Hypothalamus (VMHDM) significantly reduced conditioned freezing whereas inhibition of GABA A transmission increased this conditioned response in the AHN (Santos and Brandao, 2011). Furthermore the GABA A receptor agonists diazepam (3 and 6 mg kg −1 ) and chlordiazepoxide (10 mg kg −1 ) significantly reduced the expression of fearpotentiated startle post-training (Risbrough et al, 2003).…”

Interaction of Γ Aminobutyric Acid B Receptors and Electromagnetic Field in the Fear Response

“…Santos et al (2008) showed that GABAergic mechanisms regulate the neural systems that mediate conditioned fear. Researchers showed that inhibition of GABA transmission by GABA-synthesizing enzyme glutamic acid decarboxylase inhibitor (semicarbazide) increased fear conditioned response in the anterior hypothalamic nucleus (Santosand and Brandao, 2011). Specifically, in a conditioned fear paradigm mice deficient in the GABA B(1a) showed generalized freezing to both paired and unpaired tones (Shaban et al, 2006).…”