Sequential order spatial memory in male rats: Characteristics and impact of medial prefrontal cortex and hippocampus disruption

Episodic memory entails binding the “what”, “where”, and “when” of experiences (Tulving, 2002). In humans, it provides a link to our past and contributes to making informed decisions about future events. Learning and remembering sequences of events is crucial for survival, as almost all tasks encompass a temporal order in which behaviors must be produced. Evidence for brain mechanisms involved in episodic memory is present in a wide range of animals (Allen & Fortin, 2013). One brain area implicated in sequential order processing is the prefrontal cortex, where patients with frontal lobe damage are impaired in tasks involving temporal context, sequential order, and order recognition (Elvevåg et al., 2000, Huppert and Piercy, 1976, Hurst and Volpe, 1982, Kesner et al., 1994, Kolb and Milner, 1981, Petrides and Milner, 1982, Rizzo et al., 1996, Schwartz et al., 1991, Shimamura et al., 1990, Squire et al., 1981). Human prefrontal activity increases during temporal order memory tasks (Cabeza et al., 1997, Hsieh and Ranganath, 2015, Suzuki et al., 2002), and some dorsolateral prefrontal, premotor, and primary motor cortical neurons in monkeys have been found to encode serial order information (Barone and Joseph, 1989, Carpenter et al., 1999, Carpenter et al., 2018, Funahashi et al., 1997, Ninokura et al., 2003, Tiganj et al., 2018). Similarly, rodents with mPFC lesions were unable to process sequential order information, and mPFC neurons have been found to code for future spatial trajectories and spatiotemporal sequences (Chiba et al., 1994, Chiba et al., 1997, Euston and McNaughton, 2006, Hannesson et al., 2004, Ito et al., 2015, Kesner, 1989, Kesner and Holbrook, 1987, Mitchell and Laiacona, 1998, Tiganj et al., 2017).

The hippocampus is involved in both spatial and temporal information processing (Eichenbaum, 2014, O’Keefe and Nadel, 1978, Solomon, 1979). Human patients with hippocampal damage are impaired at temporal order memory tasks (Hopkins et al., 1995a, Hopkins et al., 1995b, Mayes et al., 2001). Similarly, rats with hippocampal lesions or pharmacological manipulation have impaired spatial and olfactory sequential order memory using food-based tasks (Agster et al., 2002, Fortin et al., 2002, Hoang and Kesner, 2008, Kesner et al., 2002, Long and Kesner, 1995). Within the rodent hippocampus, some neurons code for retrospective and prospective information (Catanese et al., 2014, Ferbinteanu and Shapiro, 2003, Frank et al., 2000, Wood et al., 2000). Furthermore, hippocampal neurons display temporal sequential firing, which may be used to predict a rat’s future navigational trajectories (Diba and Buzsáki, 2007, Dragoi and Tonegawa, 2011, Foster and Wilson, 2006, Pfeiffer and Foster, 2013). In addition to spatial coding, hippocampal neurons fire at successive moments in multiple timescales of temporally structured experiences (MacDonald et al., 2011, Mau et al., 2018, Pastalkova et al., 2008, Reddy et al., 2021), represent the sequential relationship of non-spatial odor events (Allen et al., 2016), and are modulated by the lap number on a track (Sun et al., 2020). Most research on rodent hippocampal contributions to memory are from the dorsal hippocampus (DH). The degree to which DH and ventral hippocampus (VH) are functionally integrated is unclear. There is evidence that DH processes spatial memories, whereas, VH processes odor- and anxiety-related behaviors (Strange et al., 2014). Furthermore the VH to lateral septum circuit was recently shown to encode food-based spatial memory, but not spatial memory in an escape-based procedure (Décarie-Spain et al., 2022). However, there may be an interdependence between DH and VH in information processing (Lee et al., 2019).

In the present study, we trained rats to complete a sequential order memory task using a radial eight-arm water maze. Our paradigm placed demand on sequential order memory, as rats needed to maintain where and when to choose specific escape locations. In addition, rats used allocentric visuospatial cues to swim to the hidden escape platform. The present study is an aversive task with a motivation to escape the water rather than a food-based foraging motivated task in which rats would be food restricted. Aside from the difference in motivation, the water escape task would normally be a win-stay situation, whereas, finding and consuming all the food in a location would normally be a win-shift situation where rats do not immediately return to the same location. Therefore, it is important to determine if there is comparable sequence performance under both types of motivation. Furthermore, our rats were unlikely to use olfactory cues to navigate to the correct goal location in the water maze. Well-established temporal order decision making tasks presented rats with a series of odors or spatial locations, and seconds or minutes after learning the sequential order, rats were given two options and rewarded for choosing the option that was more distant in time (Chiba et al., 1994, Fortin et al., 2002, Kesner et al., 2002, Marshuetz et al., 2000, Sugita et al., 2013). Beyond short-term durations of seconds or minutes, rats have been shown to maintain spatial temporal order memory for more than one hour (Hannesson et al., 2004). Further, rats can learn at least six sequential goal locations (Hoang & Kesner, 2008). Rats in the present study maintained their sequential order memory for a duration of five or 30 min and had the option of choosing more than two spatial locations when tested. Similar to previous sequence experiments in pigeons and monkeys (Brannon and Terrace, 1998, Orlov et al., 2000, Terrace, 1987), the current study adds an additional dimension by allowing rats to choose between multiple spatial locations within a learned spatial sequence. When presented with a sequence of items, the serial-position effect was exhibited as higher percent correct and lower latency to recall items from the beginning and end of memory lists (Murdock, 1962, Scarf and Colombo, 2008, Zhang et al., 2003). By presenting the rats with more than two spatial locations in the sequence, which included at least one prior and one future location, it enabled us to examine the degree to which rats chose prospective or retrospective locations among multiple spatial options.

In the present study, we determined the maximal sequence length learned (Experiment 1), which part of the sequence was most difficult (Experiment 2), and the effects of muscimol disruption of the mPFC, DH, VH, or combined dorsal and ventral hippocampus (DH/VH; Experiment 3).

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