Reduced fear expression after lesions of the ventral hippocampus

Abstract

The hippocampus has a critical role in several fundamental memory operations, including the conditioning of fear to contextual information. We show that the hippocampus is necessary also for unconditioned fear, and that the involved circuitry is at the ventral pole of the hippocampus. Rats with selective hippocampal lesions failed to avoid open arms in an elevated plus-maze and had decreased neuroendocrine stress responses during confinement to a brightly lit chamber. These effects were reproduced by lesions of the ventral half of the hippocampus, but not by damage to the dorsal three-quarters of the hippocampus or the amygdala. Ventral lesions failed to impair contextual fear conditioning or spatial navigation, suggesting that the ventral hippocampus may specifically influence some types of defensive fear-related behavior.defensive ͉ rat ͉ plus-maze ͉ water maze ͉ corticosterone T he experience of anxiety and fear is controlled by a modular neural system including regions in the brainstem, hypothalamus, and deeper parts of the temporal lobe (1-4). The amygdala plays a pivotal role in this system. It controls a broad range of fear reactions, and exhibits neural plasticity that may permit fear responses to be conditioned to new types of experience (refs. 1-5; but see ref. 6). Conditioned fear depends strongly on the basolateral complex of the amygdala (the lateral, basolateral, and basomedial nuclei), whereas the central nucleus and the bed nucleus of the stria terminalis are thought to be the principal output structures, mediating fear-related signals to behavioral, autonomic, and endocrine response systems in the hypothalamus and brainstem (1-5).Conditioning of fear to multimodal stimuli such as context and spatial location also requires the integrity of the hippocampus (7-9). The hippocampus is strongly involved in the encoding of spatial and episodic memories (10-12), and contextual fear conditioning is thought to require many of the associative algorithms responsible for these types of memory (13)(14)(15). Although the hippocampal influence on fear reactions may be a necessary consequence of its mnemonic operations, it is also possible that the hippocampus controls fear and anxiety independently of learning (16). This view is based particularly on the similar effects that anxiolytic drugs and septal-hippocampal lesions have on behavior in aversively motivated tasks. However, except for early studies showing that rats with large nonselective hippocampal lesions exhibit reduced food neophobia (17)(18)(19) and reduced freezing in the presence of a predator (20), direct evidence is absent. We now show (i) that the hippocampus controls defensive fear responses during exposure to a potentially threatening environment, (ii) that the relevant circuitry is located at the ventral pole of the hippocampus, and (iii) that this circuit may be dissociable from the associative circuits involved in contextual fear conditioning. Methods Subjects.A total of 187 male Long Evans rats (250-450 g) were housed individually in tran...

Temporary inhibition of dorsal or ventral hippocampus by muscimol: Distinct effects on measures of innate anxiety on the elevated plus maze, but similar disruption of contextual fear conditioning

“…This hypothesis is consistent with the idea that the ventral hippocampus plays a more important role in unconditioned anxiety than the dorsal hippocampus, which is based on wide range of evidence Bannerman et al, 2004;Pentkowski, et al, 2006;Engin & Treit, 2007). More specifically, ventral cytotoxic lesions have been found to cause more pronounced anxiolytic effects than dorsal lesions on a variety of measures of innate anxiety, including elevated plus maze measures (Kjelstrup et al, 2002;Bannerman et al, 2002Bannerman et al, , 2004, and ventral infusion of the local anaesthetic lidocaine (a sodium channel blocker inactivating neurons and fibers of passage) significantly increased the proportion of open-arm entries on the elevated plus maze test, whereas dorsal lidocaine had no significant effect (Bertoglio et al, 2006). Moreover, ventral, but not dorsal, hippocampal muscimol reduced unconditioned fear, as assessed by the shock-probe burying test (McEown and Treit, 2010).…”

“…Studies examining the effects of lesion or pharmacological manipulations of the hippocampus in rats have provided compelling evidence that the hippocampus is important for unconditioned anxiety/fear responses, as well as the formation and expression of conditioned fear responses to elemental (e.g., auditory) and contextual stimuli 1 Moreover, the weight of evidence from studies using separate ventral or dorsal hippocampal manipulations suggests that the ventral hippocampus plays a rather general role in unconditioned anxiety and conditioned fear, whereas dorsal hippocampal contributions are more restricted to specific mnemonic aspects of fear conditioning, such as context learning; this is consistent with the ventral hippocampus featuring stronger direct connectivity to amygdala and hypothalamus, key components of the brain's anxiety and fear circuit, whereas the dorsal hippocampus is more closely linked to parts of the entorhinal cortex that are implicated in visuo-spatial information encoding (Moser & Moser, 1998;Anagnostaras et al, 2001;Bast et al, 2001b;Kjelstrup et al, 2002;Bannerman et al, 2004;Maren & Holt, 2004;Pentkowski, et al, 2006;Bast, 2007;Engin & Treit, 2007;Fanselow & Dong, 2010;Bast, 2011). …”

“…Relative increases of open arm as compared to closed arm parameters are typically considered to reflect anxiolytic effects, whereas relative decreases in closed arm as compared to open arm parameters are thought to reflect anxiogenic effects (Pellow, Chopin, File, Briley, 1985;Rodgers & Dalvi, 1997; for more recent studies combining the elevated plus maze with hippocampal manipulations: Kjelstrup et al, 2002;Bannerman et al, 2002;Rezayat et al, 2005;Bertoglio et al, 2006). …”

“…Previous studies examining the effects of partial hippocampal lesions and temporary pharmacological inactivation on a range of tests of unconditioned anxiety suggested that both ventral and dorsal hippocampal inactivation may be anxiolytic, with the effects of ventral hippocampal manipulations tending to be more pronounced (Kjelstrup et al, 2002;Bannerman et al, 2002Bannerman et al, , 2004Rezayat et al, 2005;Bertoglio et al, 2006;Engin & Treit, 2007;McEown & Treit, 2010). However, the effects of hippocampal manipulations on tests of anxiety, such as the elevated plus maze, show considerable variability across studies, depending on a variety of factors (see, for example, discussion in Bannerman et al, 2002).…”

Prenatal Exposure to Betamethasone Decreases Anxiety in Developing Rats: Hippocampal Neuropeptide Y as a Target Molecule

“…Increased expression of NPY (which also has anticonvulsant features; Richichi et al, 2004) in the hippocampus may also help in explaining the slower dentate gyrus kindling rate in betamethasone-exposed immature rats compared to saline-exposed rats in our previous study (Velíšek, 2005b). Earlier studies have shown that mainly ventral but also dorsal hippocampus is involved in anxiety control (Andrews et al, 1997;Bannerman et al, 2002aBannerman et al, , b, 2003Gonzalez et al, 1998;Kjelstrup et al, 2002;McHugh et al, 2004) and NPY alterations in the hippocampus affect anxiety behaviors (Heilig, 2004;Thorsell et al, 2000). We did not see an increase in NPY expression in the basolateral amygdala; however, lesion studies have demonstrated that this region does not participate in the anxiety behavior tested in the elevated plus maze (Gonzalez et al, 1996;Treit et al, 1993), and that the amygdala is rather associated with fear control .…”