Lesions of the mammillothalamic tract and anterior thalamic nuclei: Response to Vann and Nelson (2018)

Dear Editor, We thank Vann and Nelson (2018) for providing the opportunity for further discussion on our paper, “Anterior thalamic nuclei (ATN) lesions have a greater impact than mammillothalamic tract (MTT) lesions on the extended hippocampal system”, by Perry, Mercer, Barnett, Lee and Dalrymple-Alford (2018). We contend that our findings addressed important unexplored questions concerning the effects of ATN lesions and MTT lesions. Their key point was to suggest that we have replicated previous findings on ATN and MTT lesion effects in the water-maze and radial arm maze. However, relatively few studies have examined discrete MTT lesions and there have been inconsistent findings. Our withinstudy comparison of ATN and MTT lesions obviates procedural differences between independent studies that may underpin their different findings. For example, one study examined the effects of MTT lesions on two spatial memory tasks in the water-maze and reported the opposite of what might be expected: no impairment in working memory but an impairment, albeit mild, in reference memory (Winter, Wagner, McMillin, & Wallace, 2011). A second example, by contrast, used a standard T-maze alternation procedure and MTT lesions produced a profound working memory deficit that persisted across training (Frizzati et al., 2016), despite previous testing on several other visuospatial memory tasks (Nelson & Vann, 2014). In other T-maze alternation reports, rats with MTT lesion effects have shown rapidly improving performance across repeat testing, at least for standard test procedures, whereas ATN lesions generally produce more persistent impairments (Aggleton and Nelson, 2015; Aggleton, Poirier, Aggleton, Vann, & Pearce, 2009; Loukavenko, Ottley, Moran, Wolff, & DalrympleAlford, 2007; Loukavenko, Wolff, Poirier, & Dalrymple-Alford, 2016; Ulrich, Aitken, Abraham, Dalrymple-Alford, & McNaughton, 2014; Vann & Aggleton, 2003; Vann, 2013; Warburton, Morgan, Baird, Muir & Aggleton, 1999). With respect to Vann and Nelson’s (2018) reference to mammillary body (MB) lesion studies, Vann and colleagues have elsewhere pointed out that MTT lesions provide a direct test of the functional significance of MB inputs to the ATN (Dillingham, Frizzati, Nelson, & Vann, 2015; Vann & Aggleton, 2003; Vann, 2010) whereas MB lesion studies are not optimal for this purpose due to the complexity of this region and frequent confounds with non-specific injury (Gonzalo-Ruiz, Alonso, Sanz, & Llinas, 1992; Kirk, 1998). Their second focus was that, in the abstract, we stated, “it is assumed that their (the MTT and ATN) influence on memory is functionally equivalent. ” Our sentence began by linking this comment to human anterograde amnesia, which provides the impetus for animal studies on diencephalic support of memory function. In the clinical context it is generally assumed that the core features of different examples of diencephalic amnesia are fundamentally the same and reflect disruption to the MB-ATN axis. As mentioned in our paper (Perry et al., 2018), the evidence from diencephalic amnesia as a consequence of stroke or infarct most consistently implicates MTT injury as causal for severe amnesia (e.g. Carlesimo, Lombardi, & Caltagirone, 2011; but see Duprez, Serieh, & Raftopoulos, 2005), whereas the strongest direct evidence to implicate the ATN comes from alcoholic Korsakoff patients (Kopelman, 2015). It is suggested that a greater range of impairments in the latter patient group may stem primarily from additional dysfunction, especially to the prefrontal cortex and the mediodorsal nucleus (Kopelman, 2015). Vann and Nelson (2018) also mention other extracts from our paper but incorrectly assert that we implied that all ATN function might be entirely explained by MTT and brainstem injury. Instead, our question was the degree of similarity, and severity, of ATN and MTT lesion effects in terms of memory tasks and related neurobiology. These issues are relevant given the limited and uncertain evidence from experimental MTT studies and the weight given to MTT lesions in the clinical literature. Clarity on the relative effects of ATN and MTT injury is critical to determine their potential impact for human cases of amnesia (Danet et al., 2015). Another important issue is the impact of ATN and MTT lesions on immediate early gene (IEG) activity in limbic cortex. Vann and Nelson (2018) want us to clarify that our failure to observe MTT lesion effects for zif268 expression in the deep layers of the granular b retrosplenial cortex (Rgb), and in the dysgranular retrosplenial cortex, differed from their recent report on MTT lesion effects (Frizzati et al., 2016). That study looked at zif268 in brain sections from the same rats previously examined for a c-Fos study (Vann and Albasser, 2009). However, the zif268 data in Figure 4B of Frizzati et al. (2016) did not align with their statements concerning a much larger effect of MTT lesions on c-Fos, so we avoided comment due to this uncertainty. The more important question, however, is the direct within-study comparison of MTT and ATN lesions on IEG measures in the limbic system, because previous studies have produced variable findings that depend, for example, on the time since lesion surgery and the IEG marker in question (Dumont, Amin, Poirier, Albasser, & Aggleton, 2012; Dupire et al., 2013; Jenkins, Dias, Amin, & Aggleton, 2002a; Jenkins, Dias, Amin, Brown, & Aggleton, 2002b; Jenkins, Amin, Pearce, Brown, & Aggleton, 2004; Loukavenko, Wolff, Poirier, & Dalrymple-Alford, 2016; Poirier et al., 2008;